CA3224493A1

CA3224493A1 - External anti-inflammatory coupling compound drug, and preparation method therefor and use thereof

Info

Publication number: CA3224493A1
Application number: CA3224493A
Authority: CA
Inventors: Lichun Feng; Weijiang Zhang; Guolong Wu; Hao Zhang; Dafeng LI
Original assignee: Coval Biopharma Shanghai Co Ltd
Current assignee: Coval Biopharma Shanghai Co Ltd
Priority date: 2021-07-20
Filing date: 2022-07-13
Publication date: 2023-01-26
Also published as: WO2023001045A1; KR20240027732A; WO2023001045A9; IL309840A; CN117355527A; AU2022313345A1; EP4357346A1

Abstract

An external anti-inflammatory drug compound, and a preparation method therefor and the use thereof. The structural formula of the compound is A-Y-B, wherein A is a group after dehydrogenation of an amine compound having JAK inhibitory activity, Y is a direct connection or -(CH2)-O- or , and B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B2. The compound has the special effects of having a strong transdermal property, controlled drug release, high efficacy, etc.

Description

EXTERNAL ANTI-INFLAMMATORY COUPLING COMPOUND DRUG, AND
PREPARATION METHOD THEREFOR AND USE THEREOF
Technical Field The present invention relates to an external anti-inflammatory drug, and in particular to a compound drug synthesized through coupling and use thereof.
Background Art JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signal transduction pathway, involved in cell proliferation, differentiation, apoptosis and immune regulation, and other important biological processes.
Many cytokines and growth factors signal through the JAK-STAT signaling pathway, including IL (interleukins), GM-C SF (granulocyte/macrophage colony-stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PDGF (platelet-derived factor), and IFN (interferons), among others.
The JAK-STAT signaling pathway consists of three components, a tyrosine kinase-associated receptor, a tyrosine kinase (JAK), and a transcription factor (STAT). Upon binding of the ligand to the tyrosine kinase-related receptor, the JAK bound thereto is activated. The activated JAK further activates the corresponding STAT protein. The activated STAT protein enters the nucleus to bind to a target gene and regulates the gene transcription.
The JAK family includes JAK1, JAK2, JAK3, and TYK2. These kinases control seven different STATs, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. It is precisely by controlling these STATs that cytokines and growth factors can control cell proliferation, differentiation, apoptosis, and immune regulation.
Many diseases arise from JAK and STAT mutations. By modulating and selectively inhibiting certain JAK, these diseases can be effectively treated.
Although JAK-STAT is a relatively simple signaling pathway, it is involved in many cellular functions. There are dozens of JAK inhibitors currently on the market and under research. The vast majority of JAK inhibitor programs seek to maximize efficacy and minimize side effects by selectively inhibiting one of the JAK-STAT signaling.
However, systemic administration is often unable to circumvent the contradiction between efficacy and side effects. Topical administration of JAK inhibitors may enhance efficacy while reducing systemic side effects.
Many of the JAK inhibitor programs under research also have organ selectivity as the ultimate goal to maximize efficacy/risk.
It is also an object of the present invention to maximize the therapeutic effect of dermal administration and minimize systemic toxicity by topical (dermal) administration in combination with optimization of the structure of the compound. Many skin diseases, including psoriasis, vitiligo, alopecia areata, etc. have a clear understanding of their causes and mechanisms of disease treatment. The regulatory and control mechanisms of various JAK-STATs by JAK inhibitors currently on the market and under research have also been very clear. The purpose of selective dermal administration can also be achieved by modifying the chemical structure of the currently known JAK
inhibitors to allow them to penetrate more through the protective layer of the dermal. Compared with the development of a skin-selective drug delivery formulation of a completely new compound, the product with a known compound with an optimized structure has a relatively short development cycle, low risk of efficacy failure, low possibility of unknown toxicity and low development cost.
The optimization of a compound structure by increasing compound transdermal penetration can change the physical and chemical properties of the compound by adding nonfunctional groups to the known compound structure, allowing it to penetrate more through the protective layer of the dermal. This practice is also known as prodrug technology. It is widely used in drug research and development.
Summary of the Invention The present invention is directed to the technical problem that the existing known JAK inhibitors also have high doses and side effects, and optimizes the structure of the known JAK compounds so that they can effectively achieve skin-selective administration, thereby increasing the effectiveness for skin diseases and reducing systemic dose and side effects. That is, structural optimization and skin-selective administration of known JAK inhibitors are achieved by coupling with other small molecule compounds.
Specifically, the present invention provides the following technical solutions.
1. Depending on the structure of the different JAK inhibitor compounds, specific linkers and coupling small molecules are chosen to allow more final compound (prodrug) to penetrate the protective layer of the dermal.

2. The chemical bond between the linker and the JAK inhibitor is unstable in the human skin, leading to hydrolysis and release of effective ingredients, known as JAK inhibitors.

3. The linkage between the linker and the coupled small molecule is also unstable, leading to the release of the coupled small molecule.

4. The linker is known per se as a simple chemical structure without toxicity.

5. The chemical structure of coupled small molecules is clear, and the pharmacology and toxicology are known.
Specifically, the present invention provides the following technical solutions.
In an aspect, the present invention provides an anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, having a structure shown in general formula (I):
A-Y-B (I) wherein, A is a group after dehydrogenation of an amine compound having JAK
inhibitory activity;
Y is a direct connection or-(CH2)-0-or-(CH2)-;
B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B 1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B2;
and wherein, in the case where the carboxylic acid Bi is dehydroxylated to form a group, the Y group is a direct connection or -(CH2)-0-;
in the case where the hydroxy-containing compound B2 is dehydrogenated to form a group (i.e., B is B2), the Y
group is -(CH2)-.

In a specific embodiment, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof described above, having a structure shown in general formulas (II) or (Ha):

N
N N
R2 (II) Ri a N

(ha) wherein RI is selected from pyrazolyl or pyrrolyl unsubstituted or substituted with R.; or -N(CH3)-Cy; RIa represents a pyrrole ring substituted by a halogen-substituted C
alkylaminoacyl group and/or by a C i-C6 alkyl group;
Cy is a five-or six-membered carbocyclic ring or a five-or six-membered nitrogen-containing heterocyclic ring unsubstituted or substituted by Rb; R. and Rb are each independently groups containing at least one or two groups selected from a group consisting of an acyl group, a dithioyl group, a cyano group, an amino group or a C
alkyl-substituted amino group, and a four-, five-, or six-membered nitrogen-containing heterocyclic group, or the nitrogen-containing heterocyclic group substituted with C i-C6 alkyl; preferably R. and Rb are each independently groups which consist of one group of acyl or dithioacyl and at least one group selected from a group consisting of cyano, amino or C i-C6 alkyl substituted amino, and a four-, five-, or six-membered nitrogen-containing heterocyclyl, or the nitrogen-containing heterocyclyl substituted with CI-C6 alkyl, wherein the C i-C6 alkyl is substitutable by halogen; That is, R. and Rb herein are each independently preferably a group comprising at least one acyl or dithioacyl-containing group and at least one nitrogen atom-containing group;
R2 in both general formulas (II) and (Ha) is -B, i.e. is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound Bi and is selected from R1-Ar-R3-00-, wherein R3 is selected from CI-C6 alkylene; -NH-, R5NH-, or CI-C6 alkylene substituted with a CI-C6 alkoxyamide group; or a direct connection, i.e. the Ar group is directly linked to -CO-; R3 is preferably methyl substituted or unsubstituted methylene, -C2}14-, or a direct connection; R5 is C -C6 alkylene; wherein the CI-C6 alkylene is substitutable by halogen (preferably halogen is one or two or more selected from a group consisting of fluorine, chlorine or bromine);
Ar is an aromatic ring group, preferably selected from a benzene ring; a naphthalene ring or an aryl heterocyclic ring; a benzene ring, a naphthalene ring, or an aryl heterocyclic ring or an aryl fused heterocyclic ring (here, the aryl heterocyclic ring being preferably a benzo nitrogen-containing or oxygen-containing benzo heterocyclic ring such as a benzopyrrole ring) substituted with one or more groups selected from halogen, a Ci-C6 alkyl group, a Ci-C6 alkoxy group, a Ci-C6 acyl group, or a Ci-C6 alkoxy group; Ar is more preferably an aryl heterocyclic ring containing a nitrogen atom; and R4 is halogen, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 alkyl containing Ci-C6 cycloalkanoyl, Ci-C6 alkylamido or aryl fused heterocyclic amido, Ci-C6 carbonyloxy, halogen substituted benzoyl, Ci-C6 alkyl or halogen substituted or unsubstituted phenoxy, Ci-C6 alkyl or halogen substituted or unsubstituted phenyl or aryl fused heterocyclic ring, Ci-C6 alkyl or halogen substituted or unsubstituted phenylamino, or R4 can also be absent; wherein the Ci-C6 alkoxy can also form a bridged ring with Ar.
In a specific embodiment, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof described above of the present invention, wherein Cy is substituted cyclohexyl or substituted piperidinyl; preferably, the substituted cyclohexyl group is a cyclohexyl group substituted with an amino group and a dithio group, and the substituted piperidinyl group is a piperidinyl group substituted with an acyl group or a dithio group and -CN.
Preferably, the compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention is a coupling compound resulting from a condensation reaction of an amine compound A with a carboxylic acid compound Bi.
Preferably, the compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof described above of the present invention, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups:
tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:
,0 o- CN

N-N
11.1 c4-101 N-N
0 Nr F F
CNN
I
Lt. N N N -Tofacitinib Baricitinib Oclacitinib Ruxolitinib Upadacitinib _ic() CN);
/ I
Delgocitinib;
preferably A is a group formed after dehydrogenation of tofacitinib, ruxolitinib, and baricitinib.
Still preferably, the anti-inflammatory compound or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, wherein -Bi is a group after dehydroxylation of a carboxylic acid moiety selected from a group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:
OH OH r ..,0 0 0 OH

Ibuprofen (S)-(+)-ibuprofen Naproxen Fenoprofen o OH Cl OH

F C I
Flurbiprofen Loxoprofen Ketoprofen Diclofenac 0ii 0 ---<-0----= NH ,.(OH .
N

a Etodolac Actarit N-Boc-L-phenylglycine Indomethacin H
0 N ci so N

ci-----Aspirin Indobufen Mefenamic acid Tolfenamic acid.
More preferably, the anti-inflammatory compound, or a stereoisomer, tautomer, N-oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof of the present invention, wherein the compound is a coupled compound obtained by condensation reaction of an amine compound A selected from the group consisting of tofacitinib, baricitinib, upadacitinib, oclacitinib, and ruxolitinib with a carboxylic acid compound Bi selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin; preferably, the amine compound is tofacitinib, ruxolitinib and baricitinib.
More preferably, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, wherein the compound is any one of the following specific compounds:

,õ. -.1 ,,,. ..,õ
===õcõi ----N'''L--"NrON --.H,C1-1("CN
'-Wi's-----NrCN ,N, --('-CN
,N, --,,,NrN ---No. N 4----CN ,Nõ.L.,.....ArcN

N'-- 51 51 "---1.--r\
ti=-16 N 1.(1( IN' N/ N .---ii-I) N-1*---I--- N "'L
T') kw- , .i.r N IN' 'N 'kr.:-),._ N
\ eNH 6NH 0 --4-rk>
CI

,/- -N....... H .....

- , -t5--CI ---b - / ---N--IrCN
---Nv C
N---ir-CN ''Fi '-i,r1.---r N --irCN' ---.N,Q.,1 CN
0 0 0 ...-Wa CN
----1.-. "rn N' 1,-----CN N
Win -µ. NrcN 11,1- Irs 0 N"- N /......0 0 11--W- N Win NA-n /---i -0 /.1-- -NI' N
0... e... il-_-4,....õ3 _ ._e HN 1 0 N--, li NH g s.
CI 0,1, ''....--- '

6 PCT220016CA

......p c Co c CN cp Co J d -N\-: \_., P" o' =N ON
0'%, CN
1--,1-N 4j O'S),1- _ CN OJN 0' 'N CN 0' 'N CN N-N
1---j-N
1.2.7 1-N LI-N
yx.... -N 1-4) N-N 1,...f '====
N-N
yx...
V

, y ,......\,, ../.... N ,. \
N '', \
N --- \
N '', \ N ', \ N ',. \ I1,r IN' N It.N---OT- I:N....
U. ,r LN" N U......-- -60 0 Nr - Pr . I, I

F

C---0 ;
CI
NH

c c0 /
c7.,0 ON
c 0' ,,,, CN ',0 ON 0 ..,S-o ,t ON
c c0 1.----N 0".' sN CN
L.----t1 O'Sc- CN ON -N
_,I 0' ), CN
lq) Lkil I---N
y.., k......
N-N I---N L.-N
/....) &,c.. --,...f....
N ,. \ N .*, N --;... N ----4....v.$) kir N' IN' N '', \ I:N., N ---- \ N '-= \
LO lc-r_tic?) 0 kri___ iNo II

IP H 0 0)--)...
HN
= (5-- F
N .L, N -\-\---)L.:-/':
eo oP
IN . /0 ...- 0--CI
CPD-025 CPD-026 CPD-030 * CPD-031 CPD-032

7 PCT220016CA

0 0 a a C
N crThN 1 nicnN -N Ncr'\N -N .
'N ' N cr--.1-N NcrThq-N Ncr-1 -N Nd--1-N
N ' yn NCI----N-N
y.....\
cyl,_ rk= \ &. N , \
,,1 N q---N-j--N NJ .""") rk:' \ Ni.-- >Nµ
N ''''''= "N \\
N
\
N ki /,/' 'f.j. N -1,1--H
'\ e 0 0 r) N
81)....4,H 0 - -t-c--CI * '8 b c--Pa __ 0_ \ , a a Nr\N-N NCr-)1 N NCr'l N
Nr\N-N
,......y,,x.õ\) yij...
y,,, NcrTh4-N f --\ 0 0 y NC N-N
r) N ."-- \ N '-') NN VN NCr--)1-N N
' \
k - -ry kN, k \ \
LNLN , N - LtO N --- \
ki,c N
0 N It ---r.t(?) . 0...z SO N N N4µ .")--- '-k,) NI -...-,'"
I
\ :6, A il \ _ kr( N 'NH' co HN \ , AOIN'''.E..
N- *
..._ ec, NH 0 \ ) *CI

8 PCT220016CA

'N'ssgC1 -0 ,..t .No0, 0, -N- r. 0 ,..N, .m.µssb---.0 N .-.N.si,---c,,N, 11;-.0 ,rirssicO.N, ,ft,sic...0 " SI' 'le N"-(r), N Nr ).'"------kN' N, kN1 -j>
Cr 1__i kN---N
N .. kic r kV N
H CI _ NH
0 cprIO d d-0_ , 1:3 , i , 0, N'e- 0 IVO
'''N-- ' N scO, . :vs;.--r-r) NY-4X) "'N' N '0 , N-LT) %I' N 14 Isic-0 ,H,sµno tf-LX) kV 'II' 40 Nk \
dli) 0 õ.0 H ' Gip * N\

NH
CI C). /0 *

9 N)\--- >k_NT . .
0>LN ),_.,,,,........, )\--1-F-----P1 _ F--2(110 F-7/1-14 F-2(1 F;7(1 \-----\ F411 -- \ F F
N ,N F F ---,õ F-7(11 . F
N /,,e ,,r_e---,..
c-1 ;/ N N
("LI F F r,r, yz (I
<1-11'N') III-li F F
N
N N N- CIN-1 N N /cI

Z µN-4N--4 0 0- -- , -- * = Cc"1-,-1 -- / \ ..
--\ /
0).....
CI
(r-c--__ \ /
--CI -ON

)\--N
,^f,)-11 0 0 .----A H
5, 0 F F
\--NN FF.7(Fli .-----r\ F F ¨
N,õ,N F--.7(1 ../--N ' 7'"N ,.._,NN
F---,Cri N ,N
+-N17--7--N F.---{-n (::c_, V1 F
\--N--\ Ul, j F F
cl;
N N N-N õN
el Dz r-1411 .._, _.1.-I F
F
0 1,IN N /N ----,_-,co pN)z el H C/ A
J' 0-N__. õ.0 spi___ '¨\CO FlF ( \ /,'I
N N- hre 2)-0)1_14, N N

4:2LO
cl No N N N) N 0 .._..k N\\......ko N N
N
,Ail , N
1,1-1 I I .
/N 1 i::
0-..... 0 * = Q-4\00;
T, --NH NH \
H a \ /
(------ .. 0.---CI ---\ /
0 \ /
a _ N
CI --1,1.\, 0 N 0 \\.,1 N 0 N
\---LCN ji, \õ....k.= o \--ci\

cy J N 0 ---\ I( N
rcL-1. . ,..N _N
N <fThfN
rri -a-\
,...0 = N
\--- /
cc i..,,.._.--- 3 T
H2O o N --) - -rrctsc, -0 * ,.._1 N# . -NH
.40 0 CI

More preferably, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, wherein the compound is any one of the following specific compounds:
fõ
--=Ni,µciN ---CCN 1,_,...h1 --,N,' "ir"CN --- IV''1-----,.- IN --("CN

N'F----1,\
li-N' N
k N7 NI

it NH

L)11 = -,õ,.
N'' N -CCN ----No --r-CN

CI N--Lr>., N )n LL-N----N

NH
it c, 0 ¨

007<1 0 õON
NI' y----cN

o k N N CI
/ \ H 0 \ /
CI
it 0 NN -T----µ'CN
'''N" '''-----NL----'-NCN
'"--Nrc,--'N-ii----CN N ''"-1 0 k N -'---L-N' N-FLn N'-- N LI-, -- m N

o)--- .---C) \
N

NH
ID.
CI

--.`"N'' ..--` -----. N`-------'CN

N'-------.--z--LL --- m 0 N - N-F'in ID N-----LX
LL .L.7 N.-- N
H
0 N?

HN A0.-1 ,.
\ 0 0 /o =fJ..
---1,40 CliNyCN

N--L--n '-` N
N

N
CPD-029 .

Further preferably, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, wherein the compound is one of the following specific compounds:

CN 0-- '4.11,4 -\
N-N N-N N-N
40 40 N, N

',..0 -0 s0 - ' 0- , CN
14 j 0-. 'h CN
'--- 0- 'N CN
L qJ N-N
N-N
N-N
N
N --'>
N '---- -----"\\>
11--. r LI-... -- N---''''------>
N-- m - Q N , --N

F

L. P ( (1 0.,,0 " ...0 S,--oi,S(..N3c_ JCN -' CN
co-- 45 N
N-N \

V.
N"----6-6=----,'\> N ') N'''''''.--------> Q. --Q.. P"---- N
N

>zo / \
. NH
CI
CPD-02.3 CPD-024 CPD--025 cr q., 0 ry r4 JCN
N-N
H :44 NC
,.....-N '..
N-N N
N)) N'...L.-------N),,, N
Li.--i."--"-N
11,. -'-Nr.-..---n N
N
IL iiid.' N 0 0 .
CPD-026 CPD-027 CPD-02.8 c 0' 4 JCN

N-N
V
N ----kfly ., NCr- \N-N NCr"--\N- N
N
\
N ' , ' N '''''- \ N n, N

N

NCI--\K-2-N ''N'S\,:-...%0 -, H
'-~-1- ,______\) N -.--- N
N ""-- \

r o o N N
o 0, 0 0,, H
H=== H '-r 'N
Njn N

F HN
\

,0 ,S-CN
!Lq.0 0 N-N
N N
-=
N

IP NH
N
0- * CI 14:1 CI

In another scheme of the present invention, the present invention provides an anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, having a structure shown in general formula (III):
R
N
(HI) R a ).==\
N N
(-1"
N (Ma) Rj2 wherein RI has the same meaning as RI in general formula (II); RIa has the same meaning as RIa in formula (ha);
R2' in formula (III) and formula (IIIa) are both Y-B, B is Bi in formula (II) or (Ha), or B is B2; wherein the group -Bi is a group formed by dehydroxylation of a carboxylic acid compound Bi and Y- is (CH2)-0-; the group -B2 is a group formed by dehydrogenation of a hydroxyl-containing compound B2 and Y- is-(CH2)-; the group -Bi has the same meaning as the R2 group in formula (II) or in formula (ha); the group -B2 is Re-CO-NH-Rd, wherein Re is a 4-hydroxy-benzothiazine dioxide-3-y1 represented by the following structural formula (a)( wherein the phenyl ring may be substituted by halogen or Ci-C6 alkyl), or a 4-hydroxy-Re substituted thienothiazine dioxide-3-y1 represented by the following structural formula (b), wherein -CO-NH-Rd isbonded at the 3-position of the thiazine ring, OH OH
Re ¨i--S-----"-s-N--, S--N''N- ..., .0 (a) (b) ., wherein Rd is thiazole, isothiazole, oxazole, isoxazole, or pyridine or the group thereof substituted with Ci-C6 alkyl or halogen, preferably a thiazole or isoxazole substituted with methyl;
and unsubstituted pyridyl; Re is C1-C6 alkyl or halogen (preferably halogen is one or two or more selected from a group consisting of fluorine, chlorine, or bromine); a arrow next to Re in formula (b) indicates that its substitution position on the thiophene ring may be any carbon-linked hydrogen atom capable of undergoing substitution.
More specifically, the anti-inflammatory compound or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, wherein -Bi is a group after dehydroxylation of a carboxylic acid moiety selected from a group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:
OH , .-=-:'-y0H --"C 0 S
Ibuprofen (S)-(+)-ibuprofen Naproxen Fenoprofen o 011 c I 0 2 OH H

0 OH'LJTLI 0 0 40 OH
F CI
Flurbiprofen Loxoprofen Ketoprofen Diclofenac OH
0 ----<-0 0 N . 0 \
/ --'11.- N 0 , 0H N
0 H ir ci Etodolac Actarit N-Boc-L-phenylglycine Indomethacin H
0 N CI; N

Aspirin Indobufen Mefenamic acid Tolfenamic acid -B2 is a group after dehydrogenation of a hydroxyl-containing compound of one of the following specific compounds:
OHO N - --- OHO ,INT, --, N N H H N I
S' --"' s_N
6 ,kb Meloxicam Isoxicam Piroxicam OHO %-, /
N N'' C __ / NN
1 m H I 1 m H
S----s-'" S-----s-''' // \\
o' \o o 0 Tenoxicam Lornoxicam.
Furthermore, more specifically, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, obtained by a preparation method comprising the steps of:
2) reacting A-CH2-0H compound with an acyl chloride of B or directly with the B compound;
Wherein the A-CH2-0H compound is preferably prepared by the following step 1):
reacting the amine compound A to form the A-CH2-0H compound.
More specifically, the anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof described above, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups:
tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:
Ki ,o , s-.. cr. 'N c" C
L --i--i q,, o -\, NC
sy.,._,.:--xC¨H
NI-1-n, NN-.....'"
H H H
Tofacitinib Baricitinib Oclacitinib Ruxolitinib Upadacitinib N

Nz N--"-N-H
Delgocitinib preferably A is a group formed after dehydrogenation of tofacitinib, ruxolitinib, and baricitinib.
In certain embodiments, it is preferred that A is a group formed by any one of baricitinib, oclacitinib, or upadacitinib.
Further, more specifically, the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof described above, wherein the compound is any one of the following specific compounds:

, .
L.
4.
4.
L.
L.

Y' , --...1 -.--L.,,,, IJ ------.11- C N --- N)-----}1---CCN
NL.,..õ
,.-N-TrCN --. ;1'1 ON --"---ii CN --,N,-1--,-- N-11---"-tN -Nc N 0 0 N'- 1r CN 0 0 0 1-1¨ ' LL N"="--- N
-Iq N\ 1--NF N\ k N N\
N N\ --N N\ /

CI HN / \

F
. CI
0¨
= CPD-003 CPD-082 õ ..t iõ f .0 = N--ff------CN
'."-Is L AL. ------i¨ = --q CN ,,II..._. 0 \ INV 0 \

N' a N'-' N\ ,-.N,'IL---- N--4-----CN NI N--\CN N), r--\CN

N
L D
0 11r Ki, 'it) 0 N-0, 0 -h L'0 0 N------, N S `"-- N

-N.1 0 i . 0 0 S" ----s crb a cn n >

CN
Niq j 0- `N CN
CN .S
0.5 CN
I\Llq) N-N N-N N-N Lq) yn \ \ N-N N-N
N-N
s.. N.
)\,L.... N
µ
N .'"- \ N4 '''& I\14.
N!Hsi\Nr N\ kN/ N\ N "."-- \ N 1\1 N
N \ '.11-14-\' N\ kN' k N
/

*

CPD-092 o-o 1\11qj .' ..0 .5 0` CN 0S
' CN
NLq) ,....
0 `
N-N S CN Nit_q) N-N N-N N-N
y,,,...
,Ic.,... N-N
..\__ N ''' \ N ---- \
4\'µX-.)11.- '''\ N
N \ kN-' \ N \ - \
N
kN" N\
oi N
ci / NI:.-13N 1, N-C) e,N, H

(1'6 CI

Os,, 0 - ..5S 0 9, 0 5S" 0 'N si).10, , 11 14 N'- N s:NI3 H
1,1 ) 1,1"---ir N7in N
N 'Ik----N N\ k - -o, N N\ N' N, N Ns oi oi ___O___..)._ CI___IiN / \
-- --F U-CI * 0 b Hs.NN so--'0 H OD
'le. H 0 N' N ---..1'.---k>
k c klsr N , NN' N\
oi ki NN
0 L'O 0 Is1-µ LO

,,Q--S
0' b ci,,,,,) o (N7) CI

NCI----\N-N NCF-\N-N NCF-\N-N
NC/---\N-N
4,...
NC N-N
N\ 4:fir \) \
Ny> ,...
, N
N ''-- \ N '--- \ N '-' \ N4. '''...'L-=== \\> N
, , , k - = N Q - N 7 N k N I r " r u , k N/ N 11,N.- N\
41\1µ) 0) 0) o/ 0) o/

0_ b NC N-N
NCi---N-N NC -N r-\N Nr\N-N
NC N-N N. \
..µ. \ N.
\
k N - ' (:) 4 ' ' . - f--' >kN- . .\ N N
N

0 * )L,, )--N S

S
N 0 0 N H " '`

O
/0 /0 6' sO
o"O
o CI

F
F-Arll FA/1 _ F -F:\/1 F Arl \- FAr-N
- -F F F
----\ -N,N1 F F
N / N N ,,, N N ,I1 F N, N
el )/ el j CI (¨I j CI j F
N / N
N N N N N N N N ) ea N N y o2 o) 2 0> N N

ci>
,---* 0 CI HN 0 CC--.-- 2-µ

o o o o 0 F )\---N

F -F N,,,, r\I F
- --F N N
,...2.
el / N N F
N
N
el j eX , N; eI j (ly 5/ N Ny N N N N
o2 N N ) C

0 *
0 --- ."--, i ./'0 is b is ,,c) *
CI

-.NveN1,-----cN "...r) NArk> ''vA'-'NCN ...'lealrCN '''NOCN NsCiNlr'CN
k - N Wl"i--> INI"--jr> 1.4 ON,7-----CN
N .
\I
u.... - k -- m k>
LI, -' N'Isr>
N , \-0 '----0 7'.\----= 0 4 HN * H

\L NI/

N
,,,..=C- 0 \-0 N

* * '()0 = CI
NH

õ,.
%
r._\.
\
N'"CN1 CN ____N".01 1(1 \Z\)k trCN N-- )7---\CN
N N
.-.*0 0 n 0 0 n 0 0 n N
S s- -,--di) (3"b 00 CO
CN
(/ õ0 () ,S' N-N 0' = sõ 0 rsi CN 0' = CN (. 0' 'N CN
\ Ntlqj LT
CN
,S"
0- =
NI ij- N-N
(-0 N-N N-N
L---*-- N \
\
N.
N-N 0' =
CN
(NI ."' '''''''''\> N4. '''...=..k). N --...-"- -)., L----k-N N-N
o kN N kN7 N N'''f.''')."1 \ k N'L
.Nx N .:D
. 0 * 0 * 0) N1.1 4. \ n N HN HN H 0 t1.--N-4.-L-N -\\

\--0/'''' o HN----* * * /
0 oNH
CI

(,0 .0 ,S' ,sõ
0' = CN 0 CN NI-1 j 0' = CN
NI-1 j N-N L--k.--N-N y,... N-N
N
'"-- \=> kN' N
) 0 0 n ) o0 n N "
P S n -, N
,N, " / 1 '--- NH N
S 6%NI
N H
'.µ"..- , S S' o"O 6-6 o Os Os o 0 µ
N ..õ._ H 0 "
N N H 0 ' N
W1'1.-- .s N '''.1-....\> Nr) N N ---I'''''r\>\ Q---N"" N , NN\ Q, Nr N k -- NN
\--0 /

0 * 0 0 0 N HN HN N
*0 HN---\<

H ::.....0 H C...10'N ''N"---"N
N
sSs(21:D,,r\r-Njr>
kN' N\ k , .
N '`\ k 1 \I7 N\
i N'j''. , k , N s'\ 0 0 n 0 0 n 0 0 n N
Po ''''.- N -1µ1 / , ''.= N N CI / I "--.= N
N HN---I N H N H
N H S s- ,..
b-s- -O"O 6 b 6 b C
CD
C

0 0 i---\
Nic N-N NC/"----\N-N r---.\1s1-1,1 i----N-N
NC NICI----N) N 4'.....\> N
NC
NCI--\ NN-N 4,..
4...L
N " '''= \ -***-- \
" \
---, N\.....
'' N ...\ ---' \ 2 0 li >, - P
N o 1LN-7.LN\__ kN7 N
\--0 '14' -14 0 \--o 0 H 0 /
#
0--(..._ HN HNI--\<
N# 5_0, 0 =

NCr-AN-N
NCr--\N-N NCr-'\N-N
y N ''''= \ N . - ......1\ I.L
it-hr -N \ N" N\N\
o/ o n ,--'N 'NI I II
H
s õN H
16 6 s , o' b ci µe) C) >

I, A
A
tO
U., Yj , 0 ,-, 0, r F-y )--N.N -A--N,, F.__\/¨ NI F-rF ill F H
_ .*--1.1, F_SrN F---V-HN
- - - - N , N
F F F ---, H
¨
N , N N N F
F
/ -,, N / N N õ..,õN
ea F
ca el , el j e---r- N,....,4 e------iN..,-....õ ,N 14. jr4---" re rN
N'5.
N N il N
\CI
iN--"N N N
',..
C
ri0 0 1.1 0 0 000 N -.-.Cj)rli C
NN . FIN =
= / = 0 (2 .)0 OF/c. CI = 0"---N11 6"e.

CP13.177 CPD-178 0 0 o','s, CN 9% /--FN .,)\---, F ___. F ..-\\--N,..
LA-JP' NG
NJ N
F---rII
H
_ -A7-1.4 F---r-N

F
N-N 14 N--' N;õN
F r \
N N N N 11--. , 14 ',..
Nj-r> N ---- \
w --,z= N \
N N

(1- (---1 /
11, ''. N N \
r,-----N----- N---"Nc.--- 0 N .."-- \ N
...
/ /
o ) 0) N( Ni, o o " 1 oo ---f-- 0 / a o o o S s- --, 6,....6 00 CPD.183 CPD-184 CPD-185 q 1-, al n >

0 Z¨V
_ 4-7 C=1 Z

0 0.
V
g' z "" \ f- 'i'''= .-(0. . 0), lob...0 2 2-0 z x el 11,..-.. ...,V

2 r sy / , .,0 z-uz 11:::, 0.., C.3 4.3/ -, z..) = ..- z c51N'4 Z

2 2 -. 0 0.-..
6. -- 0 - U
z--:=., 0 / ci n 2-, / Z
LizID2¨" \ _/\.c.,\N
1 z z L'\z-cd.- 0 ..

24( -,... z =-1.
ill o Flz g 0 0 Q
I¨ 5 cl=
z¨ ." \ 77.% Ã.) z---kµz z i 0.= z =-t.,:,02 0 l'i .,z \ z . / s.. ZZ¨\0 / z '0..;. 1711 2 ¨ '0 0 g 11 (.) O.
0 U a .:
I¨

" \
0.." 62 Z--"".=

2'1 N Z--1 no x ''''sz ----kt-' Z 0 / os CI 2¨ \ , z õ_, 'III

= 2 13 07,,5/ .._.
0 t_ '0.----.,,;' .=''' 0 r 0-0.

Z Z N W
01" 2 ¨'/, 2 ¨
Qz . r=-.
o cki..,jz_1!,____ z x ot, t.) 0 ,,, 0 i cr):: 111 24:02 '0 CI
a_ 0,, V
z s--. z=--.,, z/ z-k,õ, * S

41 Z ell z 0-1, ,,,,I z-, co , 0 0,/..) ,,.. , 0_ 70 .
7 r..5.1t50 u T, Z - #

2¨ = L" \ fTh, ..-0 a.
z z 0 z 0 04) /\---.----N. z=-.\
e' I-0 4, 01, Liz ,-V 0 ntii 1.0 z .- t \ ,z7\ r z-c ( zz "=-= ,.., '?

C.,' ,2 1 =-=. z.--.\
?" .g 2 ,-bz-, z *
7 0./.>
=
0 Z- - \_ f -\._ --., z 0 1 el, :
a z/' -N. z=--õ, 0 r? , O.
/
0 0 0 il O. RI> TTh'z -('- z z-==,' \ z..,,,. N., ---\
01, z 02 /I 0 z 0 r. 0, e, Fi 4/ N z-,, (1 2 2 = .

o_ 0.
O U

On the other hand, the present invention also provides a method for preparing the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, comprising the steps of:
subjecting A and B to a condensation reaction accompanied by the loss of water in the presence of a catalyst and an organic solvent.
Preferably, for the preparation method of the present invention, the catalyst is one or two or more of EDCI
(1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride)), DCC
(dicyclohexyl carbodiimide), CDI (N, N-carbonyldiimidazole), DMTMM (4-(4, 6-dimethoxytriazine)-4-methylmorpholine hydrochloride), HATU
(2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate), HCTU (6-chlorobenzotriazole-1, 1, 3, 3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) andNPC; preferably the organic solvent is one or two or more selected from a group consiting of DCM (dichloromethane), DMF (dimethylformamide), petroleum ether, acetone, chloroform, ethyl acetate, acetonitrile and THF (tetrahydrofuran), more preferably dichloromethane and/or dimethylformamide;
further preferred, the reaction is carried out in the presence of a basic substance, wherein the basic substance is preferably one or two or more selected from a group consisiting of DMAP
(dimethylamino pyridine), triethylamine, DIPEA (N, N-diisopropylethyl amine) and hydroxides or salts of sodium, potassium, lithium and ammonium.
Preferably, the method for preparing the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, comprises the steps of subjecting A-CH2OH and B to a condensation reaction on the loss of water.
Preferably, the method for preparing the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of the present invention, obtained by a preparation method comprising the steps of:
2) reacting A-CH2-0H compound with an acyl chloride of B or directly with the B compound;
wherein the A-CH2-0H compound is preferably prepared by the following step 1):
reacting the amine compound A to generate an A-CH2-0H compound.
More preferably, for the preparation process according to the invention, wherein step 1) comprises: a) adding (2-(chloromethoxy) ethyl) trimethylsilane to A in the presence of a catalyst and a solvent to generate A-CH2O-C21-14-Si(CH3)3; and b) generating A-CH2OH from A-CH2O-C21-14-Si(CH3)3 in the presence of a catalyst and a solvent; step 2) comprises: reacting A-CH2OH with an acid chloride generated from compound Bi or directly with compound B2 to generate A-CH20-B;
wherein it is preferred that in step b) the reaction is carried out in the presence of TFA (trifluoroacetic acid) as a catalyst and DCM (dichloromethane) as a solvent; or in step 2), A-CH2OH is reacted with the acid chloride generated from the compound Bi in the presence of Et3N (triethylamine) as a catalyst and DCM (dichloromethane) as a solvent or is reacted with compound B2 in the presence of PPh3 (tiphenylphosphine) and DIAD (diisopropyl azodicarboxylate) as a catalyst and THF (tetrahydrofuran) as a solvent.
Furthermore, the present invention provides a medicinal use, i.e. provides use of the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, in the preparation of anti-inflammatory drug preparations or drug compositions (preferably external drug compositions).
Furthermore, the present invention also provides an anti-inflammatory drug preparation or drug composition (preferably external drug compositions) including the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof described above.
It has been found that, by synthesizing the above compounds, the compounds of the present invention have a dissolution rate of 0.04% to 50% per day, thereby increasing the transdermal potential of known JAK inhibitors.
Brief Description of the Drawings Fig. 1 is a graph of the PASI score of an ointment prepared from CPD-029 of the present invention through skin application to treat psoriasis in a mouse model test;
Fig. 2 is a graph of the PASI score of an ointment prepared from CPD-028 of the present invention through skin application to treat psoriasis in a mouse model test;
Fig. 3 is a graph of the PASI score of an ointment prepared from CPD-027 of the present invention through skin application to treat psoriasis in a mouse model test;
Fig. 4 is a graph of the PASI score of an ointment prepared from CPD-017 of the present invention through skin application to treat psoriasis in a mouse model test; and Fig. 5 is a graph of the PASI score of an ointment prepared from CPD-002 of the present invention through skin application to treat psoriasis in a mouse model test.
Detailed Description of the Invention The present inventors have unexpectedly discovered through intensive studies that the coupling of an anti-inflammatory pharmaceutical compound containing a carboxylic acid or hydroxyl group with a JAK inhibitor compound to form a coupling compound having an acyloxy group and/or methoxy group has a high therapeutic effect and a particular effect of controlled-release pharmaceutical activity.
The anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof provided by the present invention, has a structure shown in general formula (I):
A-Y-B (I) wherein, A is a group after dehydrogenation of an amine compound having JAK
inhibitory activity;
Y is a direct connection or -(CH2)-0-;
B is a group formed by means of dehydroxylation of a carboxylic acid compound Bi with anti-inflammatory effect, or a group formed by means of dehydrogenation of a hydroxy-containing compound B2.
That is to say, the compounds of general formula (I) provided by the present invention actually include two main classes. The first main class refers to the case where A is a direct connection and the structural formula thereof is as shown in (II) or (Ha).

Ri , Ria %,--------\--N.,,:;,,N
(-1 N'N''''''' i (la) wherein RI is selected from pyrazolyl or -N(CH3)-Cy unsubstituted or substituted with Ra; RIa represents a pyrrole ring substituted a halogen-substituted CI-C6 alkylaminoacyl group and/or a CI-C6 alkyl group;
Cy is a five-or six-membered carbocyclic ring or a five-or six-membered nitrogen-containing heterocyclic ring unsubstituted or substituted by Rb; R. and Rb are each independently at least one or two groups containing an acyl group, a dithioyl group, a cyano group, an amino group or a CI-C6 alkyl-substituted amino group; preferably R. and Rb are each independently one of acyl or dithioacyl and at least one group selected from cyano, amino, or CI-C6 alkyl substituted amino, wherein the CI-C6 alkyl is substitutable by halogen;
R2 in both general formulas (II) and (Ha) is -B, i.e. is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound Bi and is selected from R1-Ar-R3-00-, wherein R3 is selected from CI-Ca alkylene; -NH-, R5NH-, or CI-C6 alkylene substituted with a CI-C6 alkoxyamide group; or a direct connection, i.e. the Ar group is directly linked to -CO-; R3 is preferably methyl substituted or unsubstituted methylene, -C2I-14-, or a direct connection; R5 is C 1 -C6 alkylene; wherein the CI-C6 alkylene is substitutable by halogen (preferably halogen is selected from one or two or more of fluorine, chlorine or bromine);
Ar is an aromatic ring group, preferably selected from a benzene ring; a naphthalene ring or an aryl heterocyclic ring; and a benzene ring, a naphthalene ring, or an aryl heterocyclic ring or an aryl fused heterocyclic ring (here, the aryl heterocyclic ring being preferably a benzo nitrogen- or oxygen-containing heterocyclic ring such as a benzopyrrole ring) substituted with a group selected from halogen, a CI-C6 alkyl group, a CI-C6 alkoxy group, a CI-C6 acyl group, or a CI-C6 alkoxy group; Ar is more preferably an aryl heterocyclic ring containing a nitrogen atom; and R6 is halogen, CI-C6 alkyl, CI-C6 alkoxy, or CI-C6 cycloalkanoyl-containing CI-C6 alkyl;
or R6 is C 1-C6 alkyl or aromatic ring or aromatic condensed ring or aromatic condensed ring heterocyclic ring containing acyl and/or amino groups, such as CI-C6 alkylamido or aryl fused heterocyclic amido, CI-C6 carbonyloxy, halogen-substituted benzoyl, CI-C6 alkyl or halogen substituted or unsubstituted phenoxy, CI-C6 alkyl or halogen substituted or unsubstituted phenyl or aryl fused heterocyclic ring, CI-C6 alkyl or halogen substituted or unsubstituted phenylamino, or R6 can also be absent; wherein the CI-C6 alkoxy can also form a bridged ring with Ar.

The aforementioned terms in the present invention, as well as all "Ci-C6"
appearing below, refer to a carbon atom number of 1-6. For example, "Ci-C6 alkyl" refers to an alkyl group with a carbon atom number of 1-6. By analogy, the terms "Ci-C6 alkoxy" and "Ci-C6 acyl" mentioned herein refer to alkoxy groups with a carbon atom number of 1-6 and groups with a carbon atom number of 1-6 containing -C=0, respectively.
"Ci-C6 alkylamide group" refers to an alkyl group containing amide groups with a carbon atom number of 1-6.
"Ci-C6 carboacyloxy group" refers to an alkyl group or cycloalkyl group containing acyloxy -00-0 with a carbon atom number of 1-6. "Ci-C6 cycloalkanoyl group" refers to a cyclic alkyl group containing -C=0 group with a carbon atom number of 1-6. The term "Ci-C6 alkyl group containing Cl-C6 cycloalkanoyl group" refers to the situation where hydrogen on carbon atoms is substituted by Ci-C6 cycloalkanoyl groups in an alkyl group with a carbon atom number of 1-6, i.e., "Ci-C6 alkyl group containing Cl-C6 cycloalkanoyl group" is equivalent to "Ci-C6 alkyl group substituted by Ci-C6 cycloalkanoyl group". The "Ci-C6" in the present invention may be specifically "C1-C6", "C1-05", "C1-C4", "C1-C3" or "C1-C2", and may also be Cl, i.e. only one carbon atom.
The first general compound described above is a compound A-B (specifically, A-B1) formed by means of dehydrogenation of an amine compound A having JAK inhibitory activity and dehydroxylation of a carboxylic acid compound Bi.
The compound of general formula (I) provided by the present invention includes the second main class of compound having a structural formula and structure shown in general formula (III):
Ri (LW
Ria N ..,;,N
N ---- re , (Ma) wherein RI has the same meaning as RI in general formula (II); Ria has the same meaning as Ria in formula (Ha);
The R2' in general formula (III) and general formula (Ma) are both -Y-B, where Y is -(CH2)-0-, and B is -Bi in general formula (II) or (Ha), i.e. group - B1 formed by the dehydroxylation of a carboxylic acid compound Bi; or B is -B2, the group -B2 is Re-CO-NH-Rd, wherein Re is a 4-hydroxy-benzothiazine dioxide-3-y1 represented by the following structural formula (a), wherein the phenyl ring is substitutable by halogen or CI-Ca alkyl, or a 4-hydroxy-Re substituted thienothiazine dioxide-3-y1 represented by the following structural formula (b), wherein -CO-NH-Rd is attached at the 3-position of the thiazine ring, OH
OH
Re /
N

= (a) (b) wherein Rd is thiazole, isothiazole, oxazole, isoxazole, or pyridine or a group thereof substituted with Ci-C6 alkyl or halogen, preferably a thiazole or isoxazole substituted with methyl; and unsubstituted pyridyl; R, is Ci-C6 alkyl or halogen (preferably halogen is selected from one or two or more of fluorine, chlorine, or bromine); the arrow next to Re in formula (b) indicates that its substitution position on the thiophene ring may be any carbon-linked hydrogen atom capable of undergoing substitution.
The second main compound of the present invention is obtained by using A-CH2OH
to undergo a condensation reaction accompanied by loss of water with B.
In particular, the preparation of the second main class of compound comprises the following steps:
2) reacting A-CH2-0H compound with an acyl chloride of B or directly with the B compound; Wherein the A-CH2-0H compound is prepared by step 1): reacting A to generate an A-CH2-0H
compound.
The scope of the compound of general formula (I) of the present invention actually also includes the various stereoisomers, tautomers, N-oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates thereof, which can be obtained by those skilled in the art according to the common knowledge, that is to say, these compounds, and the various stereoisomers, tautomers, N-oxides, metabolites, prodrugs, pharmaceutically acceptable salts or solvates thereof and the like, which can be modified by those skilled in the art according to common knowledge, can be used in the present invention to achieve the particular effects of the compounds of the present invention, such as strong transdermal performance, controllable drug release, and high efficacy, and therefore all fall within the scope of the present invention.
Examples The following is an example to illustrate how the compound of the present invention is prepared and its performance evaluation.
The NMR instrument and mass spectrometer instrument models used in Examples 1-149 below are described below, respectively:
Nuclear magnetic resonance spectrometer: Bruker 400M Nuclear Magnetic Resonance Instrument; Liquid Chromatography Mass Spectrometry Instrument: Agilent InfinityLab LC/MSD iQ
Table 1 below is a structural formula and a compound name of a target compound prepared in each example.
Table 1 Structural formulas and compound names of target compounds prepared in examples Examples Chinese name Structure (Cmpd No.) 7KirCN 3-((3R, 4R)-347-(2-(4-isobutylphenyl) N \ propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) is; N
1 (CPD-001) - (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile 0 3-((3R, 4R)-347-((S)-2-(4-isobutylphenyl) N \
propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) (methyl) 2 (CPD-002) 0 amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile 'Nss (4-((3R, N \
kkly N\ 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
3 (CPD-003) 0 0 pyrimidin-7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate Na CN 3-((3R, 4R)-3-((7-(2-((2, 3-dimethylphenyl) N \ amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin kNv N -4-y1) (methyl) 4 (CPD-004) 0 amino)-4-methylpiperidin-1-y1)-3-oxopropanen NH
itrile \seN ycN 3-((3R, 0 4R)-3-((7-(2-((3-chloro-2-methylphenyl) N'\
N amino) benzoy1)-7H-pynolo [2, 3-d]
Nv (CPD-005) 0 pyrimidin-4-y1) (methyl) NH amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile CI
3-((3R, Thqs, yCN
4R)-34(74(8)-2-(6-methoxynaphthalen-2-y1) N \
kN7 N propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) 6 (CPD-006) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanen a¨ itrile 3-((3R, 4R)-3-((7-(2-(3-benzoylphenyl) 1\1µµ N 1-rCN
propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) 7 (CPD-007) amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile 3-((3R, 4R)-3-((7-(2-(2-fluoro-[1, 1'-bipheny1]-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) (methyl) 8 (CPD-008) 0 amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile 3-((3R, 4R)-3-((7-(2-(2-(2-(2-(2, 6-dichlorophenyl) amino) phenyl) zr`l N \ acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) 9 (CPD-009) kr\r N CI
(methyl) CI amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile ss N CN 3-((3R, 4R)-4-methyl-3-(methyl NJ \ (7-(2-(3-phenoxyphenyl) kl\l N
(CPD-010) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile it 0 CN
3-((3R, 4R)-4-methyl-3-(methyl N \
N (7-(2-(4-((2-oxocyclopentyl) methyl) phenyl) 11 (CPD-011) 0 propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) 0 amino) piperidin-1-y1)-3-oxopropanenitrile 1\1µµ yCN 3-((3R, N 4R)-3-((7-(2-(1-(4-chlorobenzoy1)-5-methoxy-N
0 2-methyl-1H-indo1-3-y1) acetyl)-7H-pyrrolo [2, 12 (CPD-012) ,0 3-d] pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-l-y1)-3-oxopropanen itrile CI

No, NIrCN
N 0 N-(4-(2-(4-(((3R, N N 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) 13 (CPD-013) 0 (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin-7-y1)-2-oxoethyl) phenyl) acetamide NH
3-((3R, 4R)-3-((7-(2-(1, 8-diethyl-1, 3,4, Tr CN
0 9-tetrahydropyrano [3, 4-h]
indo1-1-y1) N
acetyl)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) 14 (CPD-014) 0 (methyl) HN
amino)-4-methylpiperidin-1-y1)-3-oxopropanen itrile 11 CN 2-(4-((3R, N \ 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N
15 (CPD-015) -0 (methyl) amino)-7H-pyrrolo [2, 3-d]
0 pyrimidine -7-carbonyl) phenyl acetate 1\1µµ YCN Tert-butyl ((S)-2-(4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) 16 (CPD-016) NH N
(methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin N , 0 0 -7-y1)-2-oxo-1-phenylethyl) carbamate .0 .S' 0' sNi_j_q)CN
(S)-2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-isobutylp henyl) propanoy1)-7H-pynolo [2, 3-d]
N-----'''',---->
17 (CPD-017) kN--N pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin O -3-y1) acetonitile s-o 0' [NI CN
Lq) (S)-2-(1-(ethylsulfony1)-3-(4-(7-(2-(6-methoxy No naphthalen-2-y1) propanoy1)-7H-pynolo [2, 18 (CPD-018) Nik 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin O -3-y1) acetonitile o--o CN
Lq) 2-(3-(4-(7-(2-(3-benzoylphenyl) N-N
\
N
propanoy1)-7H-pyrrolo [2, 3-d]
19 (CPD-019) N \
kre-N pyrimidin-4-y1)-1H-pyrazol-1 -y1)-1 -(ethylsulfo o nyl) azetidin -3-y1) acetonitile o -o -s-o- sNLTCN
2-(1-(ethylsulfony1)-3-(4-(7-(2-(2-fluoro-[1, No 1'-bipheny1]-4-y1) propanoy1)-7H-pyrrolo [2, 20 (CPD-020) N----kN----N 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin o -3-y1) acetonitile F

.0 CN
NLI...q) NN 2-(1-(ethylsulfony1)-3-(4-(7-(2-(3-phenoxyphen yl) propanoy1)-7H-pynolo [2, 3-d] pyrimidin 21 (CPD-021) N .----N.---- N -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile - S-o- = CN
14) N¨N
2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-(2-oxocyclop N"-------------- entyl) methyl) phenyl) propanoy1)-7H-pynolo 22 (CPD-022) N---N
[2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile rs,)1 2-(3-(4-(7-(2-(1-(4-chlorobenzoy1)-5-methoxy-N N .--N 2-methyl-1H-indo1-3-y1) acetyl)-7H-pyrrolo [2, ----23 (CPD-023) 3-d] pyrimidin o ----4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) / azetidin -3-y1) acetonitrile CI

-S' 0' *ON
N-N
N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfon 24 (CPD-024) N yl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pynolo [2, 3-d] pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide NH
.0 -S' 0' `NLION
2-(3-(4-(7-(2-(1, 8-diethyl-1, 3,4, N-N
9-tetrahydropyrano [3, 4-b] indol -1-y1) 25 (CPD-025) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin N
-4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) 0 azetidin -3-y1) acetonitrile HN

-S' 0' N
Tert-butyl NF (S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) 26 (CPD-026) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, N 3-d] pyrimidin -7-y1)-2-oxo-1-phenylethyl) Ni, 0 0 carbamate 0,µ
-S
N
H 0 , 14(Trans-)-447-((S)-2-(4-isobutylphenyl) 27 (CPD-027) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) H N
0 (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide NCr---.\N¨N
(R)-3-cyclopenty1-3-(4-(7-(S)-2-(4-isobutylphe 28 (CPD-028) N nyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin N
-4-y1)-1H-pyrazol-1-y1) propanenitile No' NICCN

N \
N 3-((3R, 4R)-4-methyl-3-(methyl 0 (7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) 29 (CPD-029) butanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile .0 - S,' 0' CN
1\11q) N-N
\ N 2-2-(1-(Ethylsulfony1)-3-(4-(7-(2-(4-(1-oxoisoi N
ndolin-2-y1) phenyl) butanoy1)-7H-pynolo [2, \
30 (CPD-030) k Nv N 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitile N
a NC\N-N
\ N (R)-3-cyclopenty1-3-(4-(7-((S)-2-(6-methoxyna N
phthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d]
\
31 (CPD-039) N17 N pyrimidin -4-y1))-1H-pyrazol-1-y1) propanenitrile 0¨
NC a 7-- \ N- N
(3R)-3-(4-(7-(2-(3-benzoylphenyl) N--- propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin 32 (CPD-040) k ---_.=
N N -4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanen itrile NC\N¨N
(3R)-3-cyclopenty1-3-(4-(7-(2-(2-fluoro-[1, N 1'-bipheny1]-4-y1) propanoy1)-7H-pyrrolo [2, 33 (CPD-041) 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile NC
(3R)-3-cyclopenty1-3-(4-(7-(2-(4-(1-oxoisoindo N \
lin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d]
34 (CPD-050) 0 pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile c\'µ
-s HN N
N-methy1-1-((trans)-4-(methyl 35 (CPD-065) 0 (7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) a amino) cyclohexyl) methanesulfonamide 0µµ
14(Trans)-44(7-(2-(2-fluoro-[1, 36 (CPD-056) N N 1'-bipheny1]-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 0\\
H 1-((Trans)-4-((7-(2-(1, 8-diethyl-I, 3, 4, N 9-tetrahydropyrano [3, 4-b]
indo1-1-y1) 37 (CPD-062) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) HN (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide ,S
14(Trans)-44(7-(2-(3-benzoylphenyl) 'N
38 (CPD-055) NLN propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide S
H 1-((Trans)-4-((7-((S)-2-(6-methoxynaphthalen-N
39 (CPD-054) N N 2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide o¨

.0 S
0- = CN
Niq) N¨N 2-(3-(4-(7-(2((3-Chloro-2-methylphenyl) 40 (CPD-032) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin N \
N7 N -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) 0 azetidin -3-y1) acetonitrile NH
CI
0,\
.s 14(Trans)-4((7-(2((3-chloro-2-methylphenyl) 41 (CPD-053) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin N
0 -4-y1) (methyl) amino) cyclohexyl)-N-methyl NH
methanesulfonamide ci 0,µ
1-((Trans)-4-((7-(2-(1-(4-chlorobenzoy1)-5-met 'N
hoxy-2-methy1-1H-indo1-3-y1) N N acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) 42 (CPD-060) (methyl) amino) cyclohexyl)-N-methylmethanesulfonamide CI
CI\
HON 1-((Trans)-4-((7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin 43 (CPD-052) NN
0 -4-y1) (methyl) amino) cyclohexyl)-N-methyl NH
methanesulfonamide N-methy1-1-((trans)-4-(methyl H -C;%.0 N
(7-(2-(4-((2-oxocyclopentyl) methyl) phenyl) 44 (CPD-059) Nr. N propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (2) NC N-F
\ (3R)-3-cyclopenty1-3-(4-(7-(2-(1, 8-diethyl-1, N '"-- \ 3, 4, 9-tetrahydropyran [3, 4-b] indo1-1-y1) 45 (CPD-047) kN----N
acetyl)-7H-pyrrolo [2, 3-d] pyrimidin o o -4-y1)-1H-pyrazol-1-y1) propanenitile HN
\
Tert-butyl ((S)-2-(4-(methyl c),\Q
1:),,N ((trans)-44(N-methy1su1famoy1) methyl) N"
46 (CPD-064) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
ki, N
r N H 0---\( pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate .0 -s-o- ' CN
Niq) 2-(3-(4-(7-(2-((2, 3-Dimethylphenyl) amino) N-N
\
N
benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin 47 (CPD-031) N \
kN N -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile NH

.'1\11-rCN 4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N
48 (CPD-082) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate 0¨

MV
NCN
0 (4-(((3R, kN'N 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) 49 (CPD-083) o (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate 1\1µµ if CN (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) \¨o 50 (CPD-084) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1'-bipheny1]-4-y1) propanoate (4-(((3R, 0 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N-51 (CPD-085) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin \--0 CI
-7-y1) methyl 2-(2-((2, 6-dichlorophenyl) 01 amino) phenyl) acetate Th\ls= rCN
N
0 (4-(((3R, \
N\ 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) 52 (CPD-086) 0 (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 0 -7-y1) methyl 2-(3-phenoxyphenyl) propanoate o N CN
0 (4-(((3R, N
4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) \
53 (CPD-087) 0 (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) 0 phenyl) propanoate NC N¨N
(3R)-3-cyclopenty1-3-(4-(7-(2-(3-phenoxyphen N
54 (CPD-043) NN yl) propanoy1)-7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1 -y1) propanenitrile o CN
õ,.., (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N\
0 (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 55 (CPD-088) o -7-y1) methyl 0 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1 H-indo1-3-y1) acetate CI
(4-(((3R, Th\rs N \
4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N
56 (CPD-089) " (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-acetoxybenzoate CA 03224493 2023¨ 12¨ 28 N-N (R)-3-(4-(7-(24(3-((3-2-methylphenyl) NC
amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin 57 (CPD-038) N -4-y1)-1H-pyrazol-1 -y1)-3 -cyclopentylpropanen 0 itrile NH
CI
CZ\
N-(4-(2-(4-(methyl N ((trans)-4-((N-methylsulfamoyl) methyl) )".-X"
kj 58 (CPD-061) i\ N cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide N" NyCN (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N N
59 (CPD-140) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate NH

.0 .S' 0' = CN
14) Methyl N-N
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N \ azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 60 (CPD-092) kr\l' N\
3-d] pyrimidin -7-y1) (S)-2-(4-isobutylphenyl) ,õ. propanoate o CN
No\) Methyl N-N
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N \
kNv N\ azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 61 (CPD-093) 0 3-d] pyrimidin -7-y1) (S)-2-(6-methoxynaphthalen-2-y1) propanoate .0 0 = CN
NLT
N-N
4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N \ azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, N
62 (CPD-094) N
3-d] pyrimidin -7-y1) methyl 0 2-(3-benzoylphenyl) propanoate (4-(((3R, 1\1µµ '1\j-rCN
0 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) NN (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 63 (CPD-139) -7-y1) methyl 2-(1, 8-diethyl-1, 3, 4, HN
9-tetrahydropyrano [3, 4-h] indol -1-y1) acetate (4-(((3R, rCN
4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 64 (CPD-141) N'N
\-0 0-6 -7-y1) methyl (S)-2-((tert-butoxycarbonyl) 0 0 amino)-2-phenylacetate rrCN (4-(((3R, N
4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N N
(methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 65 (CPD-136) -7-y1) methyl 2-(4-(1-oxoisoindo1-2-y1)) phenyl) butanoate N

(4-(((3R, NSNCN
4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 66 (CPD-138) 0 0 -7-y1) methyl 2-((3-chloro-2-methylphenyl) HN
amino) benzoate ci (4-(((3R, 1\1µµ '1\11rCN
0 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) NN (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 67 (CPD-137) 0 0 -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) HN
benzoate .s N-methy1-1-((trans)-4-(methyl H
'N
(7-(2-(3-phenoxyphenyl) 68 (CPD-058) N) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) * o amino) cyclohexyl) methanesulfonamide S( o 0' CN
Niq) Methyl N-F(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrmlo [2, 69 (CPD-095) k N
N 3-d] pyrimidin -7-y1) 2-(2-fluoro-[1, 1'-bipheny1]-4-y1) propanoate Methyl CN
IL1q) (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N-N
azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrmlo [2, 70 (CPD-096) N
k N\ 3-d] pyrimidin -7-y1) 2-(2-((2, Nr CI 6-dichlorophenyl) amino) phenyl) acetate CI
.S' ON Methyl o- =Ni N-N (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrmlo [2, 71 (CPD-097) N \
N1 C.; 3-d] pyrimidin -7-y1) 2-(3-phenoxyphenyl) propanoate -' 0'S =4 CN Methyl r\1, N-N
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N \ azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 72 (CPD-098) N
0 3-d] pyrimidin -7-y1) 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate o -s-- CN
Niq) Methyl N-N
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N \
ki\r N\ azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 73 (CPD-099) 3-d] pyrimidin -7-y1) 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1 o N 0 H-indo1-3-y1) acetate CI
.0 Methyl -s-o- CN
(4-(1 -(3-(cyanomethyl)-1 -(ethylsulfonyl) N-N
azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 74 (CPD-150) N \ 3-d] pyrimidin -7-y1) N\
o/ (S)-2-((tert-butoxycarbonyl) HN amino)-2-phenylacetate C (R)-3-cyclopenty1-3-(4-(7-(2-(2-((2, /-----\N¨N
NC 6-dichlorophenyl) amino) phenyl) \
N
75 (CPD-042) N acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin \
N----N CI -4-y1)-1H-pyrazol-1 -y1) propanenitile CI
.0 .S' 0' st\LI3\)CN
Methyl N¨N
\
N (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N \ azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 76 (CPD-145) N N\
---o 3-d] pyrimidin -7-y1) o 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoate Cli (3R)-3-cyclopenty1-3-(4-(7-(2-(4-((2-oxocyclop NC N¨N
entyl) methyl) phenyl) propanoy1)-7H-pyrrolo N----77 (CPD-044) [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) o propanenitrile CD
NC N-N
V (R)-N-(4-(2-(4-(1-(2-cyano-l-cyclopentylethyl) 78 (CPD-046) Nik-n N.-. N -1H- azol-4- 1 -7H- olo 2 3-d PYr Y ) PYrr [
, ]
o pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide a :
/----N (R)-3-(4-(7-(2-(1-(4-chlorobenzoy1)-5-methoxy NC N-N
\
-2-methyl- 1H-indo1-3-y1) acetyl)-7H-pynolo N ''''=- \
kN"---N1 [2, 3-d] pyrimidin 79 (CPD-045) 0 -4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanen , 0 itrile /
a a Tert-butyl r-h-N
NC
((S)-2-(4-(1-((R)-2-cyano-l-cyclopentylethyl)-80 (CPD-049) N 1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin ----H o Nr-----N N -7-y1)-2-oxo-l-phenylethyl) carbamate .0 -S' 0' ` rvq) CN Methyl N-N (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) \
N
azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 81 (CPD-147) N \
k - N 3-d] pyrimidin -7-y1) N \___(:) 0 2((3-chloro-2-methylphenyl) amino) benzoate NH
CI
Cil /-\N-N (R)-3-cyclopenty1-3-(4-(7-(2-((2, NC
N----.\ \
82 (CPD-037) 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) kN----N
0 propanenitrile HN

-S' 0' ` r\ CN Methyl LIq) N-N (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) \
N
azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 83 (CPD-146) N \
k - N 3-d] pyrimidin -7-y1) 2-((2, 3-dimethylphenyl) N \___,0 0 amino) benzoate dlNH

.0 .S' 0' CN
14) Methyl N-N
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 84 (CPD-149) kni N\
3-d] pyrimidin -7-y1) 2-(4-acetamidophenyl) o/
acetate 0.0 .S' CN Methyl -LI
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N-N
azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 85 (CPD-148) N
kNv N\ 3-d] pyrimidin -7-y1) 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indo1-1-y1) acetate H

NC /-\N-N
(4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr r\( azol-4- 1 -7H- olo 2 3-d pyrimidin -7- 1 Y ) PYrr [ PYr Y ) 86 (CPD-114) \ methyl (S)-2-(4-isobutylphenyl) propanoate (rD
NC N-N (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr azol-4-y1)-7H-pynolo [2, 3-d] pyrimidin -7-y1) 87 (CPD-115) N mo methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate .s (4-(Methyl ((trans)-4-((N-methylsulfamoyl) HN
l\k methyl) cyclohexyl) amino)-7H-pyrrolo [2, nN
88 (CPD-103) o 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate -S
(4-(Methyl ((trans)-4-((N-methylsulfamoyl) 'N
N N methyl) cyclohexyl) amino)-7H-pyrrolo [2, 89 (CPD-104) N 3-d] pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate CZ, H 'N (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 90 (CPD-105) 3-d] pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d pyrimidin -7- 1 methyl PYr Y ) 91 (CPD-162) N k__co (S)-2-((tert-butoxycarbonyl) "L\<0 amino)-2-phenylacetate (4-(Methyl ((trans)-4-((N-methylsulfamoyl) os,s µ6 methyl) cyclohexyl) amino)-7H-pyrrolo [2, N
92 (CPD-107) N 3-d] pyrimidin -7-y1) methyl 2-(2-((2, ci 0 6-dichlorophenyl) amino) phenyl) acetate a 0\\
H - ,'N,- (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, N N\
93 (CPD-158) ---0 3-d] pyrimidin -7-y1) methyl 6r,3, 2-(4-acetamidophenyl) acetate HN
c:).µ (4-(Methyl ((trans)-4-((N-methylsulfamoyl) .s HN methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1, 8-diethyl-1, 94 (CPD-157) N N
0 ) 3, 4, 9-tetrahydropyran [3, 4-h] indol -1-y1) H
acetate -o ss-0' NLii_l)CN
2-(1-(Ethylsulfony1)-3-(4-(7-(2-(4-isobutylphen N-N
yl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin 95 (CPD-033) -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-((Trans)-4-((7-(2-(4-isobutylphenyl) N
propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) 96 (CPD-051) N N
(methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 4-((4-(((3R, NI' a 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) )7"----\CN
1\1- (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin 97 (CPD-142) N
o o i -7-y1) N N
H methoxy)-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide Nr\N-N (R)-3-cyclopenty1-3-(4-(7-2-(4-isobutylphenyl) N propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin 98 (CPD-036) N N -4-y1)-1H-pyrazol-1-y1) propanenitile CI
i.-NCF-NN-N
\
N (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr N \ azol-4-y1)-7H-pyrmlo [2, 3-d]
pyrimidin -7-y1) k' 99 (CPD-116) NI
o' methyl 2-(3-benzoylphenyl) propanoate o a :
r-NN-N
NC (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr \
N
N
azol-4-y1)-7H-pyrmlo [2, 3-d] pyrimidin -7-y1) \
k7 N\
100 (CPD-117) N
/ methyl 2-(2-fluoro-[1, 1'-bipheny1]-4-y1) propanoate F

NC N-N (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyr \
\
azol-4-y1)-7H-pyrmlo [2, 3-d] pyrimidin -7-y1) N \
101 (CPD-118) kNr N methyl 2-(2-((2, 6-dichlorophenyl) amino) ) 0 phenyl) acetate CI HN
IIP CI

NC N-N
\
N (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr N \ azol-4-y1)-7H-pynolo [2, 3-d] pyrimidin -7-y1) 102 (CPD-119) kN' N\
o/ methyl 2-(3-phenoxyphenyl) propanoate o b a NC N-N
\ (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr N
N \ azol-4-y1)-7H-pynolo [2, 3-d] pyrimidin -7-y1) k7 N\
103 (CPD-120) 11 o/ methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate o o Cr]
i.-i----N-N \
NC (R)(4-(1-(2-cyano-l-cyclopentylethyl)-1H-pyra \
N
zol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) N \
kkr N\ methyl 104 (CPD-121) /

2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1 0 _ N
H-indo1-3-y1) acetate /
CI

a N
F-NN-NC \
N (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr N \ azol-4-y1)-7H-pyrmlo [2, 3-d] pyrimidin -7-y1) kN7 N
105 (CPD-163) ___01 methyl 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoate N

(117 .s, NCi-\N-N (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyr \
N
azol-4-y1)-7H-pyrmlo [2, 3-d] pyrimidin -7-y1) N \
106 (CPD-164) k , N methyl 2-((2, 3-dimethylphenyl) amino) N
\-0 benzoate HN
a NC
/----NN-N (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyr \
\
azol-4-y1)-7H-pyrmlo [2, 3-d] pyrimidin -7-y1) N \
107 (CPD-165) k , N methyl 2-((3-chloro-2-methylphenyl) amino) N
\--- 0 benzoate HN
CI

NC\N-N
\
N (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr N \ azol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 108 (CPD-184) kN' N\
o/ methyl 2-(4-isobutylphenyl) propanoate o a (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr NC N-N
\
N azol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) N \
109 (CPD-166) methyl 2-(1, 8-diethyl-1, 3,4, kNv N\

o 9-tetrahydropyran [3, 4-b] indol -1-y1) acetate N
/

r-NC --\N-N
\
N (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyr N \ azol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 110 (CPD-167) kNv N
----o methyl 2-(4-acetamidophenyl) acetate HN----\( (4-(1-((R)-2-cyano-1-cyclopentylethyl)-1H-pyr NC N-N azol-4-y1)-7H-pynolo [2, 3-d] pyrimidin -7-y1) 111 (CPD-168) methyl (S)-2-((tert-butoxycarbonyl) N \ 0 N N amino)-2-phenylacetate HN

0 -S' ' CN
_q) Methyl N-N
(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) N
azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pynolo [2, \
112 (CPD-182) N\
3-d] pyrimidin -7-y1) 2-(4-isobutylphenyl) propanoate 13,µ
-s HN (4-(Methyl ((trans)-4-((N-methylsulfamoyl) N \
methyl) cyclohexyl) amino)-7H-pyrrolo [2, N) 113 (CPD-106) 0 3-d] pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 0 1'-bipheny1]-4-y1) propanoate (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, ' 114 (CPD-108) ro) 3-d] pyrimidin -7-y1) methyl o 2-(3-phenoxyphenyl) propanoate 0õ
.s N, H 0 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 1\( N\
3-d] pyrimidin -7-y1) methyl 115 (CPD-109) 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate H (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, r N
N ) 3-d] pyrimidin -7-y1) methyl 116 (CPD-110) o 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1 0 H-indo1-3-y1) acetate CI

c;\
.s H (4-(Methyl ((trans)-4-((N-methylsulfamoyl) N
methyl) cyclohexyl) amino)-7H-pyrrolo [2, N \
117 (CPD-154) N\ 3-d] pyrimidin -7-y1) methyl 2-(4-(1-) o 0 oxoisoindolin -2-y1) phenyl) butanoate C\I\
-S
(4-(Methyl ((trans)-4-((N-methylsulfamoyl) N \ methyl) cyclohexyl) amino)-7H-pyrrolo [2, kN N\
118 (CPD-155) 3-d] pyrimidin -7-y1) methyl 2-((2, HN 3-dimethylphenyl) amino) benzoate IR\
11.S\r,`
H (4-(Methyl ((trans)-4-((N-methylsulfamoyl) N \ methyl) cyclohexyl) amino)-7H-pyrrolo [2, N7 N\
119 (CPD-183) o/ 3-d] pyrimidin -7-y1) methyl 2-(4-isobutylphenyl) propanoate c),µ
-s (4-(Methyl ((trans)-4-((N-methylsulfamoyl) H .N
methyl) cyclohexyl) amino)-7H-pyrrolo [2, N
120 (CPD-156) N 3-d] pyrimidin -7-y1) methyl HN 2((3-chloro-2-methylphenyl) amino) benzoate CI
0 CN .S' 4-((4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) ' r\Liq) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, N-N
3-d] pyrimidin -7-y1) 121 (CPD-151) N \
Nr N\ methoxy)-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide NN
_1\1 H
,S\
0' \O
0 4-((4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) s' o- = CN
Niq) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, N-N
3-d] pyrimidin -7-y1) 122 (CPD-101) N methoxy)-2-methyl-N-(5-methylthiazol-2-y1)-2 N\
H-benzo [e] [1, 2] thiazine -3-carboxamide 1, N S 1-dioxide H
/S\

(3S, 4R)-3-ethyl-4-(34(S)-2-(4-isobutylphenyl) F F
C-f propanoy1)-3H-imidazo [1, 2-a] prTolo [2, 3-e]
N-The 123 (CPD-066) pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) prTolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(34(R)-2-(4-isobutylphenyl) F
N
propanoy1)-3H-imidazo [1, 2-a] prTolo [2, 3-e]
C-f 124 (CPD-067) pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) prTolidine -1-carboxamide (3S, 4R)-3-ethy1-4-(3-(2-(2-fluoro-[1, F
CT 1'-bipheny1]-4-y1) propanoy1)-3H-imidazo [1, 125 (CPD-072) 2-a] prTolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) prTolidine -1-carboxamide (3R, 4S)-3-(3-(2-(3-benzoylphenyl) F
N
C¨f propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
NN
126 (CPD-071) o pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyiTolidine -1-carboxamide (3R, 4S)-3-(3-(2-(2-((2, 6-dichlorophenyl) F F
N N amino) phenyl) acetyl)-3H-imidazo [1, 2-a]
127 (CPD-073) pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, H
2-trifluoroethyl) pyiTolidine -1-carboxamide CI
CI

(3S, 4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl) F 1\1-1\1 F propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
N
128 (CPD-074) C¨r pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) = 0 pyiTolidine -1-carboxamide (3R, 4S)-3-(3-(2-((2, 3-dimethylphenyl) amino) F H
F F
benzoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
(-T
129 (CPD-068) pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) NH prTolne -1-carboxamide (3R, 4S)-3-(3-(2((3-chloro-2-methylphenyl) F F
N N amino) benzoy1)-3H-imidazo [1, 2-a] pyrrolo C-f 130 (CPD-069) N [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, NH 2-trifluoroethyl) prTolidine -1-carboxamide ci (3S, 4R)-3-ethy1-4-(34(S)-2-(6-) F F
N N methoxynaphthalen -2-y1) C-f NN propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
131 (CPD-070) pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) prTolidine -1-carboxamide (3S, F
F F N 4R)-3-ethyl-4-(3-(2-(4-((2-oxocyclopentyl) C¨r methyl) phenyl) propanoy1)-3H-imidazo [1, 132 (CPD-075) 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F (3R, F F 4S)-3-(3-(2-(1-(4-Chlorobenzoy1)-5-methoxy-2 N
(-f -methyl-1H-indo1-3-y1) acetyl)-3H-imidazo [1, 133 (CPD-076) 0 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide ci (3R, 4S)-3-(3-(2-(4-acetamidophenyl) F F
CN N acetyl)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e]
¨r 134 (CPD-077) NN pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide N H

(3R, 4S)-3-(3-(2-(1, 8-diethyl-1, 3, 4, 0.._,N/...\.NN 9-tetrahydropyrano [3, 4-b]
indol -1-y1) 4-NH /1\lj F
0/1 acetyl)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e]
135 (CPD-078) F F N -k H
pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) N
pyrrolidine -1-carboxamide / o )-\---N 2-(8-((3R, 4S)-4-ethy1-1-((2, 2, F-7(1 F F 2-trifluoroethyl) carbamoyl) pyrrolidin N,,.,,,N
(-T
136 (CPD-079) -3-y1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
N--re 0 pyrazine -3-carbonyl) phenylacetate o -----o o Tert-butyl ((S)-2-(8-((3R, 4S)-4-ethy1-1-((2, 2, F---.7C-H
- 2-trifluoroethyl) carbamoyl) pyrrolidin F F
NN
(-T 137 (CPD-080) -3-y1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e]
_...--0111, N----N
0 0 pyrazin -3-y1)-2-oxo-1-phenethyl) carbamate F H (3S, 4R)-3-ethy1-4-(3-(2-(4-(1-) oxoisoindolin F F
N
C-r -2-y1) phenyl) butanoy1)-3H-imidazo [1, 2-a]
NN
138 (CPD-081) 0 pynolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pynolidine -1-carboxamide 111-1 3-((3S, 4R)-6-(7-(2-(4-isobutylphenyl) CN
propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin (-)\j 139 (CPD-186) -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile 3-((3S, 4R)-6-(74(S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin 140 (CPD-187) -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile 3-((3S, 4R)-6-(74(S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin 141 (CPD-190) 0 -4-y1)-3-methyl-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) N' (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin roN
-7-y1) N-142 (CPD-090) o o methoxy)-2-methyl-N-(5-methylthiazol-2-y1)-2 N S
H H-benzo [e] [1, 2] thiazine -3-carboxamide 1, do 1-dioxide I -1 3-((3S, 4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindolin-2-y1) e0\I phenyl) butanoy1)-7H-pyrrolo [2, 3-d]
143 (CPD-201) N N
0 pyrimidin -4-y1)-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile (4-((3S, 4R)-1-(2-cyanoacety1)-3-methyl-1, 6-diazaspiro [3.4] octan -6-y1)-7H-pyrrolo [2, 144 (CPD-202) N 3-d] pyrimidin -7-y1) methyl 0 (S)-2-(4-isobutylphenyl) propanoate 3-((3S, 4R)-6-(7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin 145 (CPD-191) NN -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin CN
-7-y1) 146 (CPD-143) o n methoxy)-2-methyl-N-(pyridin-2-y1)-2H-thieno / INN
[3, 2-e] [1, 2] thiazine -3-carboxamide 1, = o"o 1-dioxide 9\ 2-Methyl-4-((4-(methyl H :144µ.0 ((trans)-4-((N-methylsulfamoyl) methyl) N( \ cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
Ny N\
147 (CPD-159) _pyrimidin -7-y1) methoxy)-N-(pyridin-2-34)-2H-benzo [e] [1, 2]
H
thiazine -3-carboxamide 1, 1-dioxide .0 4-((4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) -S-0' = CN
Niq)azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, NN
3-d] pyrimidin -7-y1) 148 (CPD-152) N \ methoxy)-2-methyl-N-(pyridin-2-y1)-2H-thieno N
- ) [3, 2-e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide FNI N
'o cZ\
H 2-Methyl-4-((4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) N \
k N7 N\ cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
149 (CPD-160) 0 0 pyrimidin -7-y1) /
N N
N H methoxy)-N-(pyridin-2-y1)-2H-thieno [3, 2-e]
\0 [1, 2] thiazine -3-carboxamide 1, 1-dioxide Example 1 3-((3R, 4R)-3-((7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile m\Iss Nvc N \
kNr N

r") N
DCC, DMAP, DCM N

N OH _______________ N
N reflux, 16 h H

Synthesis of 3-((3R, 4R)-3-((7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol) and 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 412 mg, 2 mmol) were dissolved in dichloromethane (20 mL). 4-Dimethylaminopyridine (DMAP, 134 mg, 1.1 mmol) and dicyclohexyl carbodiimide (DCC, 412 mg, 2 mmol) were added in an ice water bath, followed by stirring at reflux for 16 hours.
After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 2: 1) to give the title compound as a white solid, 0.292 g, 58% yield. MS (m/z):
[M+H] calcd for C29H36N602, 501.65;
found, 501.2.1H NMR (400 MHz, Chloroform-d) .3 8.39 (d, J= 7.3 Hz, 1H), 7.68 (dd, J= 15.2, 4.2 Hz, 1H), 7.44 ¨7.33 (m, 2H), 7.08 ¨ 7.03 (m, 2H), 6.61 (t, J= 4.2 Hz, 1H), 6.13 (if, J= 7.3, 3.5 Hz, 1H), 5.09 (s, 1H), 4.09 ¨
3.70 (m, 2H), 3.66 ¨ 3.44 (m, 4H), 3.33 (d, J= 16.4 Hz, 3H), 2.39 (d, J= 7.2 Hz, 3H), 1.88 ¨ 1.70 (m, 2H), 1.67 ¨
1.60 (m, 4H), 1.15¨ 1.03 (m, 3H), 0.86 (d, J= 6.6 Hz, 6H).
Example 2 3-((3R, 4R)-3-((7-((S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile Th\1 N
kN N

0 DCC,DMAP,DCM N
N \ OH _______ kN7 N
reflux, 16 h kkr N
I Fi Synthesis of 3-((3R, 4R)-3-((7-((S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrmlo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol) and S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 309 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). 4-Dimethylaminopyridine (DMAP, 134 mg, 1.1 mmol) and dicyclohexyl carbodiimide (DCC, 412 mg, 2 mmol) were added in an ice water bath, followed by stirring at reflux for 16 hours. After completion of the reaction, the reaction solution was filtered. The filtrate was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 2: 1) to give the title compound as a white solid, 0.24 g, 48% yield. MS (m/z): [M+H] calcd for C29H36N602, 501.65; found, 501.2.1H NMR (400 MHz, DMSO-d6) .3 8.38 (d, J = 4.6 Hz, 1H), 7.68 (dd, J = 4.3, 2.8 Hz, 1H), 7.29 (dd, J = 8.2, 2.6 Hz, 2H), 7.06 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 4.2 Hz, 1H), 6.09 (qd, J = 6.7, 3.0 Hz, 1H), 4.85 (s, 1H), 4.18 ¨ 3.59 (m, 5H), 3.41 (q, J = 5.3, 4.9 Hz, 1H), 3.24 (d, J = 2.4 Hz, 3H), 2.36 (d, J = 7.2 Hz, 3H), 1.87¨ 1.65 (m, 2H),1.63 ¨ 1.48 (m, 4H), 1.00 (dd, J = 7.2, 2.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 6H).
Example 3 (4-((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin-7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate N"' CN

N
N
\-0 First step: synthesis of 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile CI N N
N \µµ N CN S

N
\Th S i /
3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 9 g, 28.81 mmol) was dissolved in dichloromethane (180 mL) and diethyl acetate (3.745 g, 28.81 mol) under nitrogen protection. After stirring at room temperature for half an hour, (2-(chloromethoxy) ethyl) trimethylsilane (4.8 g, 28.81 mmol) was added and the stirring was continued at room temperature overnight. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further isolated by silica gel column chromatography to give the title compound as a white solid, 9 g, 71% yield. MS (m/z):
[M+H] calcd for C22H341=1602Si, 443.25;found, 443.2.
Second step: synthesis of 3-((3R, 4R)-3-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile N
N
N
\ _____________________________________________ OH
\Th S i /
Trifluoroacetic acid (6.44 g, 56.5 mmol) was slowly added dropwise to a solution of 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(timethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) piperidin-1-y1)-3-oxopropanenitrile (5 g, 11.3 mmol) in dichloromethane (100 mL) under nitrogen protection in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 24 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0 C to adjust the pH to 8. Then, the mixture was poured into a separation funnel and separated. The organic layer was washed with a saturated salt water solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title product 3.5 g, 90%
yield. MS (m/z): [M+H] calcd for C17H22N602, 343.18;found, 343.1.
Third step: synthesis of (4-((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate NNCN
Th N
N-N CI

\--OH
3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (6.63 g, 19.4 mmol), (S)-2-(4-isobutylphenyl) propanoyl chloride (8.72 g, 38.8 mmol) and triethylamine (3.93 g, 38.8 mmol) were dissolved in dichloromethane (100 mL).
After stirring at room temperature for 24 hours, the reaction mixture was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound, 4.05 g, 39.4% yield. MS (m/z): [M+H] calcd for C301-138N603, 531.67; found, 531.2.1H NMR
(400 MHz, CDC13) .3 8.32 (d, J= 7.4 Hz, 1H), 7.11 (dd, J= 12.7, 5.5 Hz, 3H), 7.03 (d, J= 7.6 Hz, 2H), 6.51 (s, 1H), 6.18 (dd, J= 10.4, 4.0 Hz, 1H), 6.14 ¨ 6.06 (m, 1H), 5.13 (s, 1H), 4.06 (dd, J= 13.2, 3.8 Hz, 1H), 3.81 (dd, J
= 18.3, 10.5 Hz, 1H), 3.69 (q, J = 7.1 Hz, 1H),3.61 (t, J= 11.8 Hz, 1H), 3.55 ¨ 3.47 (m, 2H), 3.37 (d, J= 17.9 Hz, 3H), 2.58 ¨ 2.46 (m, 1H), 2.42 (d, J= 7.1 Hz, 2H), 2.05¨ 1.91 (m, 1H), 1.83 (td, J= 13.0, 6.2 Hz, 2H), 1.45 (d, J
= 7.1 Hz, 3H), 1.28 (s, 1H), 1.09 (dd, J= 12.9, 7.1 Hz, 3H), 0.88 (d, J= 6.6 Hz, 6H).
Example 4 3-((3R, 4R)-3-((7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 0 CDI,DCM N \
N
N 111111111 K2CO3,DMF kN7 N

NH
3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 314 mg, 1.3 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a yellow solid, 0.1 g, yield 18.6%. MS (m/z): [M+H]
calcd for C311-133N702, 536.65;
found, 536.2.1H NMR (400 MHz, DMSO) .3 8.60 (d, J = 16.4 Hz, 1H), 8.14 (d, J =
7.5 Hz, 1H), 7.55 ¨ 7.43 (m, 1H), 7.35 (dt, J = 17.9, 8.5 Hz, 2H), 7.06 (d, J = 6.2 Hz, 2H), 6.98 (s, 1H), 6.87 (t, J = 12.4 Hz, 1H), 6.80 (d, J =
8.4 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 4.86 (s, 1H), 4.20 ¨ 3.90 (m, 3H), 3.87 ¨ 3.64 (m, 2H), 3.42 (s, 1H), 3.30 (s, 3H), 2.39 (d, J = 5.3 Hz, 1H), 2.26 (s, 3H), 2.10 ¨ 1.96 (m, 3H), 1.90¨ 1.67 (m, 1H), 1.66 ¨1.53 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H).
Example 5 3-((3R, 4R)-3-((7-(2-((3-chloro-2-methylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile CN
fl ,ON
0 OH Nµ

0 CDI,DCM N -7C=
+ CI
= kNv N
N K2CO3,DMF

NH
CI
3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 187 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.6 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tofenamic acid, 204 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a yellow solid, 0.12 g, 35.9% yield. MS
(m/z): [M+H] calcd for C301-130C1N702, 557.07; found, 557.2.1H NMR (400 MHz, DMSO-d6) .3 8.23 (d, J = 17.2 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.46 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 7.43-7.34 (m, 2H), 7.07 (tq, J = 7.0, 4.8, 3.6 Hz, 3H), 6.96 (d, J = 8.3 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.84 (d, J =
4.1 Hz, 1H), 4.84 (s, 1H), 4.19-3.90 (m, 3H), 3.74 (dtd, J = 34.8, 14.2, 13.1, 7.4 Hz, 2H), 3.50-3.39 (m, 1H), 3.29-3.21 (m, 3H), 2.46-2.32 (m, 1H), 2.06 (d, J = 8.5 Hz, 3H), 1.92-1.66 (m, 1H), 1.64-1.51 (m, 1H), 1.03 (d, J = 7.1 Hz, 3H).
Example 6 3-((3R, 4R)-3-074(S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile N\s'ON ycN

N"O
N \
Nv N

0¨

-ff- CN 0 EDCI DCM
0v N
HO rt, 16 h ¨
Synthesis of 3-((3R, 4R)-34(74(S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrmlo [2, 3-d] pyrimidin -4-y1)-piperidin-l-y1]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 506 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 863 mg, 4.5 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 2) to give the title compound as a white solid, 0.7 g, 66.8% yield. MS (m/z): [M+H] calcd for C30H32N603, 525.63; found, 525.3.1H NMR
(400 MHz, DMSO) .3 8.41 (s,1H), 7.81 - 7.69 (m,4H), 7.50 (dd, J= 7.0, 5.3 Hz,1H), 7.24 (s,1H), 7.12 (dd, J= 8.9, 2.3 Hz,1H), 6.88 (d, J =
3.7 Hz,1H), 6.25 - 6.16 (m,1H), 4.83 (s,1H), 4.17 - 3.87 (m,3H), 3.84 (s,3H), 3.72 - 3.59 (m,2H), 3.41 - 3.39 (m,1H), 3.23 (s,3H), 2.32 (d, J= 13.3 Hz,1H), 1.83 - 1.49 (m,5H), 0.99 (d, J=
7.1 Hz,3H) Example 7 3-((3R, 4R)-3-((7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile N\SNCN

N
N

EDCI,DCM
OH

rt, 24h 0 - H
Synthesis of 3-((3R, 4R)-3-((7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 559 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 2) to give the title compound as a white solid, 0.73 g, 66.6% yield. MS (m/z): [M+H] calcd for C32H32N603, 549.65; found, 549.3.1H NMR
(400 MHz, DMSO) .3 8.33 (d, J= 7.4 Hz,1H), 7.79 (d, J= 1.6 Hz,1H), 7.76 - 7.63 (m,5H), 7.61 (d, J= 7.8 Hz,1H), 7.57 (d, J= 8.5 Hz,1H), 7.54 (s,1H), 7.51 (d, J= 7.7 Hz,1H), 6.94 (d, J= 3.8 Hz,1H), 6.16 (q, J= 6.8 Hz,1H), 4.85 (s,1H), 4.14 - 3.90 (m,3H), 3.83 -3.60 (m,2H), 3.46 - 3.39 (m,1H), 3.26 (s,3H), 2.44 -2.29 (m,1H), 1.90- 1.68 (m,1H), 1.67- 1.51 (m,4H), 1.02 (t, J = 9.4 Hz,3H).
Example 8 3-((3R, 4R)-3-((7-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile NNICCN

N

F
y-s-c1.1 õ
-==== No CN
11.-N N
EDCI,DCM

rt. 24 h 0 HO
N
N H
Synthesis of 3-((3R, 4R)-3-((7-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 537 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 2) to give the title compound as a white solid, 0.73 g, 67.8% yield. MS (m/z): [M+H] calcd for C311-131FN602, 539.63; found, 539.2.1H
NMR (400 MHz, DMSO) .3 8.41 (dd, J= 5.7, 1.3 Hz,1H), 7.72 (d, J= 4.2 Hz,1H), 7.54 -7.43 (m,5H), 7.41 -7.27 (m,3H), 6.93 (s,1H), 6.16 (q, J
= 6.7 Hz,1H), 4.84 (s,1H), 4.16 - 3.99 (m,2H), 3.98 - 3.87 (m,1H), 3.75 - 3.59 (m,2H), 3.45 - 3.39 (m,1H), 3.23 (s,3H), 2.43 -2.27 (m,1H), 1.88- 1.66 (m,1H), 1.65- 1.52 (m,4H), 1.04 - 0.93 (m,3H).
Example 9 3-((3R, 4R)-3-((7-(2-(2-(2-(2-(2, 6-dichlorophenyl) amino) phenyl) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile N,N = N CN

N
N CI

CI
'Nµµ 1\11rCN
CI OH EDCI,DCM N

N N CI
rt, 24 h N N
N H 111" CI HN
CI
Synthesis of 3-((3R, 4R)-3-((7-(2-(2-(2-(2-(2, 6-dichlorophenyl) amino) phenyl) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-(2, 6-dichlorophenylamino) phenylacetic acid (diclofenac, 651 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a white solid, 0.25 g, 21.2% yield. MS (m/z): [M+H] calcd for C30H29C12N702, 590.51; found, 590.2.1H
NMR (400 MHz, DMSO) 8.41 (d, J= 5.9 Hz,1H), 7.75 (d, J= 4.1 Hz,1H), 7.51 (d, J= 8.1 Hz,2H), 7.35 (d, J= 12.7 Hz,1H), 7.28 (d, J= 7.0 Hz,1H), 7.20 (t, J= 8.1 Hz,1H), 7.07 (t, J= 7.7 Hz,1H), 6.96 (d, J= 3.8 Hz,1H), 6.83 (t, J= 7.4 Hz,1H), 6.22 (d, J
= 8.0 Hz,1H), 4.99 - 4.83 (m,3H), 4.16 - 3.99 (m,3H), 3.88 - 3.61 (m,2H), 3.40 (d, J= 14.4 Hz,1H), 3.29 (s,3H), 2.45 - 2.29 (m,1H), 1.89- 1.67 (m,1H), 1.65 - 1.52 (m,1H), 1.01 (d, J= 7.1 Hz,3H).
Example 10 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile N\SNCN

N

Au 0 OH EDCI,DCM LNN

0 rt, 20 h 0 N
N H

Synthesis of 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 781 mg, 2.5 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 787.4 mg, 3.25 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 720.5 mg, 3.75 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a white solid, 1.1 g, 82% yield. MS (m/z): [M+H] calcd for C311-132N603 537.64; found, 537.3.1H NMR
(400 MHz, Chloroform-d) 8.30 (dd, J= 10.4, 4.8 Hz, 1H), 7.77 ¨ 7.61 (m, 1H), 7.36 ¨ 7.16 (m, 5H), 7.10 (t, J= 7.4 Hz, 1H), 6.98 ¨6.92 (m, 2H), 6.83 (dt, J= 7.7, 2.0 Hz, 1H), 6.62 (t, J= 4.2 Hz, 1H), 6.10 (qd, J= 7.0, 4.5 Hz, 1H), 5.09 (ddq, J= 14.2, 9.9, 4.8 Hz, 1H), 4.12¨ 3.67 (m, 2H), 3.63 ¨3.41 (m, 4H), 3.33 (d, J= 15.6 Hz, 3H), 2.48 (ddt, J= 17.9, 12.9, 5.9 Hz, 1H), 1.93 (dddd, J= 17.4, 12.6, 7.5, 3.9 Hz, 1H), 1.81 ¨ 1.68 (m, 1H), 1.66¨
1.58 (m, 3H), 1.08 (dd, J= 12.6, 7.1 Hz, 3H).
Example 11 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) amino) piperidin-1-y1)-3-oxopropanenitrile N CN

N \
kN7 N

0 0 EDCI,DCM N
N \
krs,r N 0 OH rt, 6 h Synthesis of 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 624 mg, 2 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl]
propanoic acid (loxoprofen, 541 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a white solid, 0.48 g, 44.4% yield. MS (m/z): [M+H] calcd for C311-136N603, 541.67; found, 541.3.1H
NMR (400 MHz, DMSO) .3 8.38 (dd, J= 6.2, 1.5 Hz, 1H), 7.80 ¨ 7.60 (m, 1H), 7.32 (dd, J= 17.9, 16.2 Hz, 2H), 7.10 (d, J= 7.9 Hz, 2H), 6.89 (d, J
= 4.3 Hz, 1H), 6.19 ¨ 5.98 (m, 1H), 4.84 (s, 1H), 4.17 ¨ 3.98 (m, 2H), 3.96 ¨
3.57 (m, 3H), 3.40 (t, J = 5.9 Hz, 1H), 3.21 (s, 3H), 2.94 ¨ 2.83 (m, 1H), 2.41 ¨ 2.25 (m, 3H), 2.25 ¨ 2.14 (m, 1H), 2.09 ¨ 2.02 (m, 1H), 1.90 ¨
1.80 (m, 3H), 1.72¨ 1.48 (m, 5H), 1.48 ¨ 1.37 (m, 1H), 1.07 ¨ 0.93 (m, 3H).
Example 12 3-((3R, 4R)-3-07-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile N = N N

N
m N

CI
OH
NCN
N .õõo 0 "Nrµ
EDCI,DCM 0 N N
N \ rt, 4 h tcr N 0 0 - H

CI

CI
Synthesis of 3-((3R, 4R)-3-07-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1H-indole-3-acetic acid (indomethacin, 233 mg, 0.65 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 2: 3) to give the title compound as a white solid, 0.16 g, 49.1% yield. MS (m/z): [M+H] calcd for C35H34C1N704, 653.15;
found,653.3 NMR (400 MHz, DMSO-d6) .3 8.45 (d, J= 6.4 Hz, 1H), 7.77 ¨ 7.61 (m, 5H), 7.11 (t, J= 2.8 Hz, 1H), 6.97 (t, J= 6.7 Hz, 2H), 6.71 (dd, J= 9.1, 2.5 Hz, 1H), 5.05 ¨4.86 (m, 3H), 4.21 ¨ 3.89 (m, 3H), 3.86 ¨ 3.64 (m, 5H), 3.46 ¨ 3.40 (m, 1H), 3.31 (s, 3H), 2.44 ¨ 2.38 (m, 1H), 1.88 ¨ 1.52 (m, 2H), 1.32¨ 1.21 (m, 3H), 1.02 (d, J= 7.1 Hz, 3H).
Example 13 N-(4-(2-(4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin-7-y1)-2-oxoethyl) phenyl) acetamide 1\lµsµ CN
NO
N N

C;1.N H

0 0 EDCI,DCM
+ 0 N rt, 3 h 0 H
NH
Synthesis of N-(4-(2-(4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide 3-{(3R, 4R)-4-methyl-34methyl-(7H-pyrmlo [2, 3-d] pyrimidin -4-y1)-piperidin-l-y1]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 126 mg, 0.65 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 6) to give the title compound as a white solid, 0.118 g, 48.6% yield. MS
(m/z): [M+H] calcd for C26H29N703, 488.56; found,488.2.11-1 NMR (400 MHz, DMSO-d6) .3 9.90 (s, 1H), 8.39 (d, J= 5.8 Hz, 1H), 7.70 (d, J= 4.1 Hz, 1H), 7.51 (d, J= 8.1 Hz, 2H), 7.26 (d, J=
8.1 Hz, 2H), 6.94 (d, J= 4.4 Hz, 1H), 4.97 ¨ 4.71 (m, 3H), 4.24 ¨ 3.89 (m, 3H), 3.85 ¨3.59 (m, 1H), 3.49¨ 3.40 (m, 1H), 3.28 (s, 3H), 2.39 (q, J=
6.2 Hz, 1H), 2.03 (s, 3H), 1.88 ¨ 1.46 (m, 2H), 1.02 (d, J= 7.0 Hz, 3H).
Example 14 3-((3R, 4R)-3-07-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indo1-1-y1) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin-4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile N
m N

H N
I,õ CN
\ 0 0 EDCI,DCM

N \ OH rt, 24 h 0 HN
Synthesis of 3-((3R, 4R)-3-((7-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indol -1-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 156 mg, 0.5 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole -1-acetic acid (etodolac, 158 mg, 0.55 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 2) to give the title compound as a white solid, 0.11 g, 37.8% yield. MS (m/z): [M+H] calcd for C33H39N703, 582.72;
found,582.3.1H NMR (400 MHz, DMSO-d6) .3 10.50 (s, 1H), 8.29 (s, 1H), 7.67 (td, J= 4.5, 2.2 Hz, 1H), 7.23 (dd, J= 7.5, 2.0 Hz, 1H), 6.98 ¨ 6.81 (m, 3H), 4.84 (s, 1H), 4.67 (ddd, J= 14.7, 8.6, 6.3 Hz, 1H), 4.20 ¨ 3.98 (m, 3H), 3.98 ¨3.82 (m, 2H), 3.81 ¨3.61 (m, 3H), 3.47¨ 3.38 (m, 1H), 3.27 (s,3H), 2.84 (q, J= 7.5 Hz, 2H), 2.60 (dt, J= 9.4, 4.7 Hz, 2H), 2.45 ¨2.30 (m, 1H), 2.16 (qq, J= 6.9, 4.5, 3.9 Hz, 2H), 1.83 (s, 2H), 1.26 (td, J= 7.6, 3.1 Hz, 3H), 1.01 (dt, J= 7.2, 2.8 Hz, 3H), 0.69 (td, J= 7.1, 3.4 Hz, 3H).
Example 15 2-(4-((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidine -7-carbonyl) phenyl acetate ,CN
-N ICCN

N \
Nv N

,õ.
Ir'CN
.1\1µµCIN

0 EDCI,DCM
0 N \
N \
OH rt, 14 h 11-Nr' N
N

/(3 Synthesis of 2-(4-((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidine -7-carbonyl) phenyl acetate 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 2-acetoxybenzoic acid (aspirin, 216 mg, 1.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 2) to give the title compound as a white solid, 0.06 g, 12.6% yield. MS (m/z): [M+H] calcd for C25H26N604, 475.52; found,475.2.1H NMR
(400 MHz, DMSO-d6) 8.02 (d, J= 6.8 Hz, 1H), 7.69 ¨7.57 (m, 2H), 7.58 (d, J= 4.1 Hz, 1H), 7.43 ¨7.36 (m, 1H), 7.29 (d, J= 8.1 Hz, 1H), 6.98 (t, J= 5.0 Hz, 1H), 4.84 (s, 1H), 4.19 ¨ 3.87 (m, 3H), 3.84 ¨ 3.62 (m, 2H), 3.44 ¨ 3.29 (m, 1H), 3.28 (s, 3H), 2.37 (dq, J= 12.0, 6.7, 5.6 Hz, 1H), 1.92 (d, J= 1.7 Hz, 3H), 1.88 ¨ 1.66 (m, 1H), 1.58 (p, J= 8.0, 7.0 Hz, 1H), 1.01 (d, J= 7.1 Hz, 3H).
Example 16 tert-butyl ((S)-2-(4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate NI\µµ CN

N
NH
N
iN

NH

OH
EDCI,DCM

rt, 5 h kNH

Synthesis of tert-butyl ((S)-2-(4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), N-Boc-L-phenylglycine (326 mg, 1.3 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 2) to give the title compound as a white solid, 0.3 g, yield 55%. MS (m/z): [M+H]+ calcd for C29H35N704, 546.64; found, 546.3.1H NMR
(400 MHz, DMSO-d6) 8.38 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.70 (d, J = 4.1 Hz, 1H), 7.48 (t, J = 7.4 Hz, 3H), 7.35-7.21 (m, 3H), 7.02-6.83 (m, 1H), 4.86 (s, 1H), 4.08-3.97 (m, 3H), 3.82-3.54 (m, 2H), 3.42-3.39 (m, 1H), 3.24 (s, 3H), 2.35 (s, 1H), 1.81-1.56 (m, 2H), 1.39 (s, 9H), 1.06-0.90 (m, 3H).
Example 17 (S)-2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-isobutylp hen yl) prop anoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile .0 .S' 0' CN
N¨N
N N
0, .S
0' ' CN
14) N-N
N-N
0 EDCI,DMAP,DCM
OH rt, 3 h N
N

Synthesis of (S)-2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylamino pyridine (DMAP, 488mg, 4 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 453 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 576 mg, 3 mmol) was dissolved in dichloromethane (20 mL) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
2: 1 to 1: 2) to give the title compound as a white solid, 0.5 g, 44.7% yield. MS (m/z): [M+H] calcd for C29H33N703S, 560.69; found, 560.2.1H NMR (400 MHz, Chloroform-d) .3 8.96 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.03 (d, J = 4.2 Hz, 1H), 7.47 ¨ 7.34 (m, 2H), 7.06 (d, J= 7.9 Hz, 2H), 6.81 (d, J= 4.1 Hz, 1H), 6.06 (q, J=
6.9 Hz, 1H), 4.62 (d, J= 9.2 Hz, 2H), 4.34 ¨ 4.16 (m, 2H), 3.40 (s, 2H), 3.08 (q, J= 7.4 Hz, 2H), 2.39 (d, J=
7.2 Hz, 2H), 1.80 (dp, J= 13.5, 6.8 Hz, 1H), 1.68 (d, J= 6.9 Hz, 3H), 1.41 (t, J= 7.4 Hz, 3H), 0.95 ¨0.82 (m, 6H).

Example 18 (S)-2-(1-(ethylsulfony1)-3-(4-(7-(2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 0' CN
lq) N -N
N
N

0' JCN
-S' 0" CN
N-N
N-N 1- H EDCI,DMAP,DCM

rt, 16 h N N

-Synthesis of (S)-2-(1-(ethylsulfony1)-3-(4-(7-(2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 305 mg, 2.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (Naproxen, 230 mg, 1.1 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
1: 1 to 1: 2) to give the title compound as a white solid, 0.25 g, 42.9% yield. MS (m/z): [M+H] calcd for C301-129N7045, 584.67; found, 584.2.1H NMR (400 MHz, DMSO) .3 9.03 (s,1H), 8.98 (s,1H), 8.49 (s,1H), 8.18 (d, J= 4.2 Hz,1H), 7.85 (s,1H), 7.80- 7.74 (m,2H), 7.58 -7.54 (m,1H), 7.40 (d, J= 4.2 Hz,1H), 7.25 (d, J= 2.2 Hz,1H), 7.12 (dd, J= 9.0, 2.4 Hz,1H), 6.12 (q, J= 6.8 Hz,1H), 4.58 (d, J= 9.2 Hz,2H), 4.23 (d, J= 9.2 Hz,2H), 3.83 (s,3H), 3.68 (s,2H), 3.23 (q, J= 7.3 Hz,2H), 1.68 (d, J= 6.9 Hz,3H), 1.24 (t, J= 7.3 Hz,3H).

Example 19 2-(3-(4-(7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin-4-y1)-1H-pyrazol-1-y1)-1-(ethyls ulfonyl) azetidin -3-y1) acetonitrile .S'0 0' ' CN
N-N
N
N-...---N

,o ,s--,o o' , CN
Niq) .S' Nc 0" ' CN q) N¨N
NN.,) N¨N 0 EDCI,DMAP,DCM
LO + cilJQH

0 rt, 3 h k ni N¶

Synthesis of 2-(3-(4-(7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 244 mg, 2 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 280 mg, 1.1 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
2) to give the title compound as a white solid, 0.2 g, 32.9% yield. MS (m/z): [M+H] calcd for C32H29N704S, 608.69; found, 608.3.1H NMR (400 MHz, DMSO) .3 9.00 (s,1H), 8.93 (s,1H), 8.51 (s,1H), 8.17 (d, J = 4.2 Hz,1H), 7.81 (s,1H), 7.76 (d, J = 7.7 Hz,1H), 7.70 ¨ 7.58 (m,4H), 7.52 (t, J= 7.6 Hz,3H), 7.43 (d, J= 4.2 Hz,1H), 6.06 (q, J= 6.8 Hz,1H), 4.59 (d, J=
9.1 Hz,2H), 4.24 (d, J= 9.1 Hz,2H), 3.68 (s,2H), 3.23 (q, J= 7.3 Hz,2H), 1.63 (d, J= 6.9 Hz,3H), 1.24 (t, J= 7.3 Hz,3H).
Example 20 2-(1-(ethylsulfony1)-3-(4-(7-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile S' lq) N¨N
N
NN

-s=-o- CN
,o 14) -S' N-N
O
Nt_q CN_ N-N EDCI,DMAP,DCM N

HO

Synthesis of 2-(1-(ethylsulfony1)-3-(4-(7-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylamino pyridine (DMAP, 610 mg, 5 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 537 mg, 2.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1:
2) to give the title compound as a white solid, 0.3 g, 25.1% yield. MS (m/z): [M+H] calcd for C311-128 FN7035, 598.67; found, 598.2.1H NMR (400 MHz, DMSO) .3 9.05 (s,1H), 9.02 (s,1H), 8.53 (s,1H), 8.20 (d, J= 4.2 Hz,1H), 7.54¨ 7.35 (m,9H), 6.08 (q, J=
7.0 Hz,1H), 4.61 (d, J= 9.2 Hz,2H), 4.25 (d, J= 9.2 Hz,2H), 3.70 (s,2H), 3.24 (q, J= 7.4 Hz,2H), 1.66 (d, J= 7.0 Hz,3H), 1.25 (t, J= 7.3 Hz,3H).
Example 21 2-(1-(Ethylsulfony1)-3-(4-(7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-py razol-1-y1) azetidin -3-y1) acetonitrile o CN
N¨N
N
N

.0 0- = CN
-0 Nqj 0' CN
r\LIsq) N¨N

OH EDCI,DMAP,DCM
rt, 17 h Synthesis of 2-(1-(ethylsulfony1)-3-(4-(7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 133 mg, 0.55 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 17 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1:
2) to give the title compound as a white solid, 0.11 g, 74.5% yield. MS (m/z): [M+H] calcd for C311-129N7045, 596.68; found,596.2.1H NMR (400 MHz, DMSO-d6) .3 8.99 (s, 1H), 8.86 (s, 1H), 8.50 (s, 1H), 8.12 (d, J= 4.2 Hz, 1H), 7.40 (d, J= 4.2 Hz, 1H), 7.37 ¨7.25 (m, 3H), 7.21 ¨7.10 (m, 2H), 7.07 (t, J= 2.1 Hz, 1H), 6.95 ¨ 6.89 (m, 2H), 6.86 ¨ 6.78 (m, 1H), 5.94 (d, J
= 6.9 Hz, 1H), 4.60 (d, J= 9.1 Hz, 2H), 4.24 (d, J= 9.1 Hz, 2H), 3.68 (s, 2H), 3.23 (q, J= 7.3 Hz, 2H), 1.57 (d, J
= 6.9 Hz, 3H), 1.24 (t, J= 7.4 Hz, 3H).
Example 22 2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-(2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile .0 S' 1\11q) N¨N
N
N

-s-o" CN
.0 0' = CN N-N
NI j N-N 0 EDCI,DMAP,DCM
c) OH _________ _ N

rt, 17 h N N
N

Synthesis of 2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-(2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 136mg, 0.55 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 17 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 3:4) to give the title compound as a white solid, 0.13 g, 43.4% yield. MS (m/z): [M+H]
calcd for C311-133N7045, 600.71;
found,600.3.11-1 NMR (400 MHz, DMSO-d6) .3 8.99 (d, J = 3.4 Hz, 2H), 8.50 (s, 1H), 8.14 (d, J = 4.2 Hz, 1H), 7.40 (d, J= 4.2 Hz, 1H), 7.34 (d, J= 7.9 Hz, 2H), 7.12 (d, J= 7.9 Hz, 2H), 5.98 (q, J= 6.9 Hz, 1H), 4.59 (d, J=
9.1 Hz, 2H), 4.24 (d, J= 9.1 Hz, 2H), 3.69 (s, 2H), 3.33 ¨3.19 (m, 2H), 2.96 ¨2.83 (m, 1H), 2.44 ¨ 2.27 (m, 2H), 2.20 (dd, J= 18.5, 8.5 Hz, 1H), 2.03 (ddd, J= 18.6, 10.1, 8.6 Hz, 1H), 1.95 ¨
1.74 (m, 2H), 1.70¨ 1.61 (m, 1H), 1.58 (d, J= 6.9 Hz, 3H), 1.42 (dd, J= 10.6, 6.9 Hz, 1H), 1.24 (dd, J= 8.7, 6.1 Hz, 3H).
Example 23 2-(3-(4-(7-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile O' "
N ¨ N
N
N

CI
CN
-S' 0' µNL4)CN OH N-N

EDCI,DMAP,DCM N
rt, 20 h N

N

CI

Synthesis of 2-(3-(4-(7-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 197 mg, 0.55 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 5) to give the title compound as a white solid, 0.18 g, 50.6% yield. MS (m/z): [M+H] calcd for C35H31C1N805S, 712.19; found,711.2.1H
NMR (400 MHz, DMSO-d6) .3 9.05 (d, J= 2.4 Hz, 2H), 8.56 (s, 1H), 8.17 (d, J= 4.2 Hz, 1H), 7.77 ¨ 7.61 (m, 4H), 7.47 (d, J= 4.2 Hz, 1H), 7.18 (d, J= 2.6 Hz, 1H), 6.99 (d, J= 9.0 Hz, 1H), 6.72 (dd, J= 9.0, 2.6 Hz, 1H), 5.04 (s, 2H), 4.64 (d, J= 9.1 Hz, 2H), 4.28 (d, J= 9.1 Hz, 2H), 3.71 (d, J= 6.8 Hz, 5H), 3.25 (q, J= 7.3 Hz, 2H), 2.27 (s, 3H), 1.26 (t, J= 7.3 Hz, 3H).
Example 24 N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide .0 lq) N¨N
N-------kkr N

0' *CN
0' *CN N-N
N-N OH
0 EDCI,DMAP,DCM
+ 1{

rt, 14 h N
m 0 N
0.NH
Synthesis of N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide 1-(Ethylsulfony1)-344-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 106 mg, 0.55 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and DMF
(2 mL) and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 2) to give the title compound as a white solid, 0.03 g, 10% yield. MS (m/z):
[M+H] calcd for C26H261\18045, 547.61;
found,547.3.11-1 NMR (400 MHz, DMSO-d6) .3 9.93 (s, 1H), 9.01 (d, J= 10.0 Hz, 2H), 8.53 (s, 1H), 8.14 (d, J=
4.2 Hz, 1H), 7.54 (d, J= 8.1 Hz, 2H), 7.44 (d, J= 4.2 Hz, 1H), 7.30 (d, J= 8.0 Hz, 2H), 4.87 (s, 2H), 4.62 (d, J=
9.0 Hz, 2H), 4.26 (d, J= 9.1 Hz, 2H), 3.71 (s, 2H), 3.25 (q, J= 7.3 Hz, 2H), 2.04 (s, 3H), 1.26 (t, J= 7.4 Hz, 3H).
Example 25 2-(3-(4-(7-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indol -1-y1) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile .0 S' N¨N
N
N

H N

' 0"SN-N CN
,o -S' 0' 1\4 CN
N-N N
\ 0 0 EDCI,DCM
OH rt, 6 h 0 N

HN
Synthesis of 2-(3-(4-(7-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b]
indo1-1-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitile (baricitinib, 186 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole-1 -acetic acid (etodolac, 158 mg, 0.55 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1:1) to give the title compound as a white solid, 0.18 g, 56% yield. MS (m/z): [M+H]
calcd for C33H36N804S, 641.76;
found,641.2.1H NMR (400 MHz, DMSO-d6) .3 10.59 (s, 1H), 9.04 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 8.15 (d, J=
4.2 Hz, 1H), 7.44 (d, J= 4.2 Hz, 1H), 7.27 (dd, J= 7.4, 1.6 Hz, 1H), 7.00 ¨6.88 (m, 2H), 4.71 ¨4.56 (m, 3H), 4.29 (d, J= 9.1 Hz, 2H), 4.22 (d, J= 14.5 Hz, 1H), 3.91 (ddd, J= 11.7, 7.1, 4.9 Hz, 1H), 3.83 ¨3.76 (m, 1H), 3.74 (s, 2H), 3.27 (q, J= 7.3 Hz, 2H), 2.89 (q, J= 7.5 Hz, 2H), 2.64 (dt, J= 6.8, 4.2 Hz, 2H), 2.21 (q, J= 7.2 Hz, 2H), 1.29 (td, J= 7.4, 4.3 Hz, 6H), 0.76 (t, J= 7.3 Hz, 3H).
Example 26 Tert-butyl (S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate S' N¨N
N
N N

-o 0' NE_j_q)CN
0' `NE.q.õCN N-N
N-N
EDCI,DMAP,DCM

rt, 16 h N

Synthesis of tert-butyl (S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H
-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitile (baricitinib, 371 mg, 1 mmol), N-Boc-L-phenylglycine (301.5 mg, 1.2 mmol), 4-dimethylamino pyridine (DMAP, 183 mg, 1.5 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 2) to give the title compound as a white solid, 0.12 g, 19.8% yield. MS (m/z): [M+H] calcd for C29H32N805S, 605.69; found,605.3.11-1 NMR (400 MHz, DMSO-d6) 9.00 (d, J= 3.7 Hz, 2H), 8.51 (s, 1H), 8.18 (d, J= 4.1 Hz, 1H), 7.99 (d, J=
7.5 Hz, 1H), 7.61 ¨7.37 (m, 4H), 7.36 ¨7.23 (m, 3H), 4.60 (d, J= 9.1 Hz, 2H), 4.24 (d, J= 9.1 Hz, 2H), 3.69 (s, 2H), 3.23 (q, J= 7.3 Hz, 2H), 1.40 (s, 9H), 1.24 (t, J= 7.4 Hz, 3H).

Example 27 4R)-4-((7-((S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 0\\
H =-=
'N
N
N N

,s N
H

EDCI,DMAP,DCM
OH
rt, 16 h N N

N-methyl-1-((1R, 4R)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 338 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 122 mg, 1 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol) and 143-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 2: 1) to give the title compound as a white solid, 0.14 g, 26.6% yield. MS (m/z):
[M+H] calcd for C28H39N5035, 526.71; found, 526.2.1H NMR (400 MHz, DMSO-d6) .3 8.36 (s, 1H), 7.66 (d, J=
4.2 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.06 (d, J= 7.8 Hz, 2H), 6.93 ¨6.79 (m, 2H), 6.10 (q, J= 6.9 Hz, 1H), 4.63 (s, 1H), 3.14 (s, 3H), 2.94 (d, J=
6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.35 (d, J= 7.2 Hz, 2H), 2.04 (d, J=
13.1 Hz, 2H), 1.88 ¨ 1.74 (m, 2H), 1.74 ¨ 1.63 (m, 4H), 1.52 (d, J= 7.0 Hz, 3H), 1.27 ¨ 1.21 (m, 2H), 0.81 (d, J=
6.6 Hz, 6H).
Example 28 (R)-3-cyclopenty1-3-(4-(7-(S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-py razol-1-y1) propanenitrile N¨ N
NC
N
N

NCNN
1,0 NC
EDCI,DMAP,DCM
OH rt, 5 h N

(R)-3-(4-(7h-pyrmlo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (ruxolitinib, 306 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 3:
1) to give the title compound as a white solid, 0.42 g, 85% yield. MS (m/z): [M+H] calcd for C30H341\1604, 495.64; found, 495.2.1H NMR (400 MHz, DMSO-d6) .3 8.96 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.11 (d, J= 4.2 Hz, 1H), 7.36 ¨ 7.27 (m, 3H), 7.07 (d, J= 8.0 Hz, 2H), 6.00 (q, J= 6.9 Hz, 1H), 4.53 (td, J= 9.6, 4.3 Hz, 1H), 3.23 (qd, J= 17.1, 6.9 Hz, 2H), 2.47 ¨
2.38 (m, 1H), 2.34 (d, J= 7.1 Hz, 2H), 1.77 (ddd, J= 27.2, 12.6, 7.2 Hz, 2H), 1.66¨ 1.47 (m, 5H), 1.47¨ 1.11 (m, 5H), 0.88 ¨ 0.76 (m, 6H).
Example 29 3-((3R, 4R)-4-methyl-3-(methyl (7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) amino) piperidin -1-y1)-3-oxopropanenitrile Nrs' N ICCN

N \

MA's r\r N

N \ EDCI,DMAP, DCM N

3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-piperidin-1-y1]-3-oxo-propionitrile (tofacitinib, 312 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 384 mg, 1.3 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 249 mg, 1.3 mmol) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 5) to give the title compound as a white solid, 0.27 g, 45.8% yield. MS (m/z):
[M+H] calcd for C34H35N703, 590.70;
found,590.2.1H NMR (400 MHz, DMSO-d6) .3 8.52¨ 8.37 (m, 1H), 7.84 (d, J= 8.1 Hz, 2H), 7.74 (dd, J= 22.3, 5.9 Hz, 2H), 7.66 (d, J= 7.1 Hz, 2H), 7.57 ¨ 7.50 (m, 1H), 7.50 ¨7.44 (m, 2H), 6.90 (d, J= 4.6 Hz, 1H), 6.01 ¨
5.91 (m, 1H), 4.97 (s, 2H), 4.84 (s, 1H), 4.18 ¨4.00 (m, 2H), 3.99 ¨ 3.53 (m, 3H), 3.41 (d, J= 6.3 Hz, 1H), 3.24 (s, 3H), 2.43 ¨2.30 (m, 1H), 2.27 ¨ 2.14 (m, 1H), 1.95 ¨ 1.50 (m, 3H), 1.00 (d, J=
7.1 Hz, 3H), 0.91 (t, J= 7.3 Hz, 3H).
Example 30 2-2-(1-(Ethylsulfony1)-3-(4-(7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile cO
0' CN
Ntlq) N-N
\
N
N \

N

-S-O' ' CN
NL.q) N-N

N
.0 N '"=- \
.S\-.
0' CN kNv N

+ N EDCI,DMAP DCM , 0 rt, 20h N- - - ''' ' = ''= - - - ''- N 0 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 354 mg, 1.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 288 mg, 1.5 mmol) was dissolved in dichloromethane (15 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
5: 1 to 1:1) to give the title compound as a white solid, 0.46 g, 70.9% yield. MS (m/z): [M+H] calcd for C34F132N8045, 649.74;
found,649.3.1H NMR (400 MHz, DMSO) .3 9.05 (s, 1H), 8.98 (s, 1H), 8.50 (s, 1H), 8.16 (d, J= 3.9 Hz, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.73 (t, J= 14.0 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.52 (d, J=
8.4 Hz, 3H), 7.40 (d, J= 3.9 Hz, 1H), 5.85 (t, J = 7.2 Hz, 1H), 4.96 (s, 2H), 4.59 (d, J= 9.0 Hz, 2H), 4.24 (d, J= 9.0 Hz, 2H), 3.68 (s, 2H), 3.22 (dd, J= 14.5, 7.2 Hz, 2H), 2.26 (dt, J= 13.8, 7.1 Hz, 1H), 1.94 (dd, J= 13.6, 7.2 Hz, 1H), 1.23 (dd, J= 14.8, 7.6 Hz, 3H), 0.94 (t, J= 7.1 Hz, 3H).
Example 31 (R)-3-cyclopenty1-3-(4-(74(S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1))-1H-pyrazol-1-y1) propanenitrile r-N-N
NC
N \
N
N

NC N-N
NC N-N
0 EDCI,DMAP,DCM
HO rt, 16 h N \
11,N' N
N \

(R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 6 mg, 0.05 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 138 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1:
2) to give the title compound as a white solid, 0.16 g, 61.7% yield. MS (m/z): [M+H] calcd for C311-130N602, 519.62; found, 519.3.1H NMR (400 MHz, DMSO) .3 8.99 (s, 1H), 8.85 (s, 1H), 8.39 (s, 1H), 8.14 (d, J= 4.2 Hz, 1H), 7.84 (s, 1H), 7.81 ¨7.73 (m, 2H), 7.55 (dd, J= 8.6, 1.5 Hz, 1H), 7.30 (d, J= 4.2 Hz, 1H), 7.24 (d, J= 2.2 Hz, 1H), 7.11 (dd, J= 9.0, 2.4 Hz, 1H), 6.13 (q, J= 6.8 Hz, 1H), 4.53 (td, J= 9.6, 4.2 Hz, 1H), 3.83 (s, 3H), 3.29¨
3.14 (m, 2H), 2.47 ¨2.34 (m, 1H), 1.81 (td, J= 11.7, 7.3 Hz, 1H), 1.68 (d, J= 6.9 Hz, 3H), 1.63 ¨ 1.38 (m, 4H), 1.38¨ 1.21 (m, 3H).
Example 32 (3R)-3-(4-(7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-3-cy clopentylpropanenitrile NCNN

NC N-N
N
NC "Th 0H EDCI,DMAP,DCM N
0 rt, 16h 0 N \ 0 - N
N H
(R)-3-(4-(7h-pynolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 6 mg, 0.05 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 152 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1 to 1: 1) to give the title compound as a white solid, 0.18 g, 66.4% yield. MS (m/z): [M+H] calcd for C33H30N602, 543.64;
found, 543.2.1H NMR (400 MHz, DMSO) .3 8.89 (d, J= 6.4 Hz, 2H), 8.41 (s, 1H), 8.14 (d, J= 4.2 Hz, 1H), 7.82 (s, 1H), 7.76 (d, J= 7.7 Hz, 1H), 7.70 ¨ 7.59 (m, 4H), 7.53 (t, J= 7.6 Hz, 3H), 7.33 (d, J= 4.1 Hz, 1H), 6.08 (q, J= 6.8 Hz, 1H), 4.55 (td, J= 9.6, 4.2 Hz, 1H), 3.29¨ 3.16 (m, 2H), 2.42 (dt, J= 17.0, 8.5 Hz, 1H), 1.82 (td, J=
11.6, 7.3 Hz, 1H), 1.70¨ 1.39 (m, 7H), 1.39¨ 1.20 (m, 3H).
Example 33 (3R)-3-cyclopenty1-3-(4-(7-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile N-N
NC
N

NC?
NC N-N HO N N
0 EDCI,DMAP,DCM

rt, 16 h N \
N
(R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 6 mg, 0.05 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 146 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1:
2) to give the title compound as a white solid, 0.17 g, 63.9% yield. MS (m/z): [M+H] calcd for C32H29FN60, 533.62; found, 533.2.1H NMR (400 MHz, DMSO) .3 9.00 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.15 (d, J= 4.1 Hz, 1H), 7.52 ¨ 7.29 (m, 9H), 6.08 (q, J=
6.7 Hz, 1H), 4.54 (td, J= 9.4, 4.0 Hz, 1H), 3.28 ¨ 3.15 (m, 2H), 2.43 (dd, J=
16.9, 8.4 Hz, 1H), 1.87¨ 1.76 (m, 1H), 1.70¨ 1.38 (m, 7H), 1.38¨ 1.20 (m, 3H).
Example 34 (3R)-3-cyclopenty1-3-(4-(7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile F-NN-N
NC
N \
kN7 N

NC
N \
N

r-N-N

EDCI,DMAP,DCM
0 rt, 16h NN

(R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (ruxolitinib, 153 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 6 mg, 0.05 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 177 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1:1) to give the title compound as a white solid, 0.17 g, 58.3% yield. MS (m/z): [M+H] calcd for C35H33N702, 584.70; found,584.3.1H NMR (400 MHz, DMSO) .3 9.01 (s, 1H), 8.86 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 4.2 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.75 (d, J= 7.6 Hz, 1H), 7.70 ¨7.59 (m, 2H), 7.52 (t, J= 7.0 Hz, 3H), 7.30 (d, J= 3.9 Hz, 1H), 5.86 (t, J= 7.4 Hz, 1H), 4.96 (s, 2H), 4.53 (td, J= 9.5, 4.2 Hz, 1H), 3.28 ¨3.14 (m, 2H), 2.41 (dt, J=
17.2, 8.5 Hz, 1H), 2.25 (td, J= 14.2, 7.2 Hz, 1H), 1.97¨ 1.88 (m, 1H), 1.80 (dt, J= 11.9, 5.8 Hz, 1H), 1.65¨ 1.39 (m, 3H), 1.36¨ 1.21 (m, 4H), 0.94 (t, J= 7.3 Hz, 3H).

Example 35 N-methyl-1-((trans)-4-(methyl (7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d] pyri midin -4-y1) amino) cyclohexyl) methanesulfonamide C\I\

N \
kN' N

,s HN N.--HO

N \
CZ\ N
HO,, 0 N
NHO
(N-methyl-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 230 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1:1) to give the title compound as a white solid, 0.22 g, 59.7% yield. MS (m/z): [M+H]
calcd for C33H38N6045, 615.77;
found,615.3.1H NMR (400 MHz, DMSO) .3 8.41 (s, 1H), 7.83 (d, J= 8.3 Hz, 2H), 7.76 (d, J= 7.4 Hz, 1H), 7.67 (dd, J= 9.6, 5.5 Hz, 3H), 7.59 ¨ 7.42 (m, 3H), 6.92 ¨ 6.73 (m, 2H), 5.97 (t, J= 7.1 Hz, 1H), 4.96 (s, 2H), 4.64 (s, 1H), 3.14 (s, 3H), 2.94 (d, J= 5.8 Hz, 2H), 2.57 (t, J= 9.7 Hz, 3H), 2.26 ¨
2.13 (m, 1H), 2.03 (d, J= 12.0 Hz, 2H), 1.97 ¨ 1.77 (m, 2H), 1.68 (s, 4H), 1.37¨ 1.13 (m, 2H), 0.90 (dd, J= 18.8, 11.8 Hz, 3H).
Example 36 1-((Trans)-4-((7-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide \
N `0 H
N
N N

HO
Cpµµ
H m N -+

N
N H
N-methyl-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 191 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 1: 2) to give the title compound as a white solid, 0.22 g, 65.1% yield. MS (m/z):
[M+H] calcd for C301-134FN5035, 564.69; found, 564.3.1H NMR (400 MHz, DMSO) .3 8.39 (s, 1H), 7.70 (d, J = 4.2 Hz, 1H), 7.52 ¨ 7.41 (m, 5H), 7.35 (dt, J= 19.2, 7.4 Hz, 3H), 6.92 ¨ 6.82 (m, 2H), 6.17 (q, J= 6.8 Hz, 1H), 4.64 (s, 1H), 3.16 (s, 3H), 2.94 (d, J
= 6.2 Hz, 2H), 2.59 (d, J= 4.9 Hz, 3H), 2.04 (d, J= 12.5 Hz, 2H), 1.85 (s, 1H), 1.65 (d, J= 26.0 Hz, 4H), 1.59 (d, J= 7.0 Hz, 3H), 1.37 ¨ 1.19 (m, 2H).
Example 37 14(Trans)-4-07-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indo1-1-y1) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide H
'N
N N

HN
HN
HO
\S:10 0 N
H
EDCI,DMAP,DCM NN

HN

HN
N-methy1-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole -1-acetic acid (etodolac, 224 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) was dissolved in dichloromethane (15 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 3: 1 to 1:1) to give the title compound as a white solid, 0.23 g, 63.2% yield. MS (m/z): [M+H] calcd for C32H42N604S, 607.79; found, 607.3.1H
NMR (400 MHz, DMSO-d6)

10.47 (s, 1H), 8.27 (s, 1H), 7.64 (d, J= 4.2 Hz, 1H), 7.22 (dd, J= 7.4, 1.6 Hz, 1H), 6.98 ¨6.78 (m, 4H), 4.66 (d, J
= 14.6 Hz, 2H), 4.03 (d, J= 7.5 Hz, 1H), 3.89 (s, 1H), 3.76 (dt, J= 10.7, 4.4 Hz, 1H), 3.16 (s, 3H), 2.94 (d, J= 6.2 Hz, 2H), 2.84 (q, J= 7.5 Hz, 2H), 2.59 (t, J= 3.8 Hz, 5H), 2.15 (ft, J= 7.2, 4.6 Hz, 2H), 2.09 ¨ 2.01 (m, 2H), 1.85 (t, J= 7.5 Hz, 1H), 1.69 (s, 4H), 1.35¨ 1.21 (m, 5H), 0.68 (t, J= 7.3 Hz, 3H).
Example 38 1-((Trans)-4-((7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 0\\
H
N
NO;

H oH EDCI,DMAP,DCM N
0 rt, 16h 0 m 0 N
N-methyl-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 198 mg, 0.78 mmol) and 143-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a white solid, 0.17 g, 49.4% yield. MS (m/z):
[M+H] calcd for C31H35N5045, 574.71; found, 574.3.1H NMR (400 MHz, DMSO-d6) .3 8.30 (s, 1H), 7.78 (t, J=
1.9 Hz, 1H), 7.74 ¨ 7.57 (m, 6H), 7.52 (dt, J= 11.6, 7.7 Hz, 3H), 6.86 (t, J= 4.9 Hz, 2H), 6.16 (q, J= 6.9 Hz, 1H), 4.64 (s, 1H), 3.15 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.04 (d, J= 13.0 Hz, 2H), 1.84 (dq, J= 13.3, 6.8 Hz, 1H), 1.68 (d, J=
8.5 Hz, 4H), 1.58 (d, J= 7.0 Hz, 3H), 1.28 (s, 2H).
Example 39 14(Trans)-44(7((S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 0\\
H
N

0¨

NN
H
0,µ
N
H
N EDCI,DMAP,DCM N) " OH _______________________________________ 16 h N

N-Methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 180 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:1) to give the title compound as a white solid, 0.23 g, 69.8% yield. MS (m/z): [M+H] calcd for C29H35N504S, 550.69; found, 550.4.1H
NMR (400 MHz, DMSO-d6) 8.39 (s, 1H), 7.78 (d, J= 7.8 Hz, 1H), 7.74 (t, J= 8.9 Hz, 2H), 7.68 (d, J=
4.1 Hz, 1H), 7.50 (dd, J= 8.5, 1.3 Hz, 1H), 7.23 (d, J= 2.1 Hz, 1H), 7.11 (dd, J= 8.9, 2.4 Hz, 1H), 6.87 (q, J= 4.5 Hz, 1H), 6.79 (d, J= 3.0 Hz, 1H), 6.21 (q, J= 6.8 Hz, 1H), 4.61 (s, 1H), 3.83 (s, 3H), 3.10 (s, 3H), 2.93 (d, J=
6.2 Hz, 2H), 2.59 (d, J= 4.8 Hz, 3H), 2.06¨ 1.98 (m, 2H), 1.83 (s, 1H), 1.63 (t, J= 9.3 Hz, 7H), 1.36 ¨ 1.15 (m, 2H).
Example 40 2-(3-(4-(7-(2-((3-Chloro-2-methylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyraz ol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile ,C) -S' Ntlq) N-N
\
N
N \
Nr N

NH
CI
...s-o- = CN
0 4 j ,S-- CN N-N

L---- 0 OH c) N-N H N .'"= \
N \ + CI N
N 0 0 kN N

k , 'CI
1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitile (baricitinib, 371 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 313 mg, 1.2 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1:1) to give the title compound as a white solid, 0.22 g, 35.7% yield. MS (m/z): [M+H]
calcd for C301-127C1N8035, 616.11;
found,616.3.1H NMR (400 MHz, DMSO-d6) .3 8.99 (s, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 7.83 (d, J=
4.1 Hz, 1H), 7.50 (dd, J= 8.3, 6.5 Hz, 2H), 7.37 (d, J= 4.1 Hz, 1H), 7.09 -7.04 (m, 3H), 7.00 -6.90 (m, 2H), 4.61 (d, J= 9.1 Hz, 2H), 4.25 (d, J= 9.1 Hz, 2H), 3.70 (s, 2H), 3.24 (q, J=
7.3 Hz, 2H), 2.01 (s, 3H), 1.25 (t, J=
7.4 Hz, 3H).
Example 41 1-((Trans)-4-((7-(2-((3-chloro-2-methylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 0\\
H

NH
CI
9\
"

EDCI,DMAP
CI
N DCM
N

NH
CI
N-methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 203 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 73 mg, 0.6 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 204 mg, 0.78 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a yellow solid, 0.2 g, 57.4% yield. MS
(m/z): [M+H] calcd for C29H33C1N6035, 581.20; found, 581.4.1H NMR (400 MHz, DMSO-d6) .3 8.24 (s, 1H), 8.08 (s, 1H), 7.45 (dd, J= 11.4, 4.2 Hz, 1H), 7.41 ¨ 7.22 (m, 2H), 7.14 ¨7.01 (m, 3H), 6.96 (d, J= 8.3 Hz, 1H), 6.93 ¨6.75 (m, 3H), 4.63 (s, 1H), 3.17 (s, 3H), 2.95 (d, J= 6.1 Hz, 2H), 2.60 (d, J= 4.9 Hz, 3H), 2.13 ¨2.01 (s, 5H), 1.89 (d, J= 22.2 Hz, 1H), 1.78¨ 1.62 (m, 4H), 1.36¨ 1.24 (m, 2H).
Example 42 14(Trans)-4-07-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indo1-3-y1) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methylmethanesulfonamide 9\
H

CI
OH

H N EDCI DMAP,DCM
' N

N

CI
Synthesis of 1-((trans)-4-07-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methy1-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide N-methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 233 mg, 0.65 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a yellow solid, 0.14 g, 41.4% yield. MS
(m/z): [M+H] calcd for C34H37C1N6055, 677.22; found, 677.3 .1H NMR (400 MHz, DMSO-d6) .3 8.42 (s, 1H), 7.76 ¨ 7.60 (m, 5H), 7.11 (d, J= 2.6 Hz, 1H), 6.98 (d, J= 9.0 Hz, 1H), 6.89 (dt, J= 9.9, 4.5 Hz, 2H), 6.71 (dd, J=
9.0, 2.6 Hz, 1H), 4.99 (s, 2H), 4.69 (s, 1H), 3.69 (s, 3H), 3.20 (s, 3H), 2.96 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 4.9 Hz, 3H), 2.24 (s, 3H), 2.06 (d, J= 12.6 Hz, 2H), 1.87 (dt, J= 15.5, 5.8 Hz, 1H), 1.72 (dt, J= 8.5, 5.0 Hz, 4H), 1.41 ¨
1.27 (m, 2H).
Example 43 1-((trans)-4-((7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (3\\
H

NH
H 17'0 H , EDCI, DMAP,DCM
'N N dal N N N
41-ff 0 Nv = NH
Synthesis of 1-((trans)-4-((7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide N-methy1-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 157 mg, 0.65 mmol), and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 7 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a yellow solid, 0.17 g, 60.7% yield. MS (m/z):
[M+H] calcd for C301-136N6035, 561.26;
found, 561.3.1H NMR (400 MHz, DMSO-d6) .3 8.59 (s, 1H), 8.12 (s, 1H), 7.48 (d, J= 4.0 Hz, 1H), 7.43 ¨7.28 (m, 2H), 7.13 ¨ 6.96 (m, 3H), 6.92 ¨ 6.79 (m, 3H), 6.77 ¨ 6.66(m, 1H), 4.82 ¨4.49 (m, 1H), 3.19 (s, 3H), 2.95 (d, J=
6.2 Hz, 2H), 2.59 (d, J= 4.9 Hz, 3H), 2.27 (d, J= 9.8 Hz, 3H), 2.07 (d, J=
21.6 Hz, 5H), 1.92¨ 1.82 (m, 1H), 1.72 (h, J= 3.3 Hz, 4H), 1.37¨ 1.26 (m, 2H).
Example 44 N-methyl-1-((trans)-4-(methyl (7-(2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide 9\
H
kNN

''HN-C10 HON0 OH EDCI, DMAP,DCM
N

N

Synthesis of N-methyl-1-((trans)-4-(methyl (7-(2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide N-methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 160 mg, 0.65 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a white solid, 0.2 g, 70.7% yield. MS (m/z): [M+H] calcd for C301-139N5045, 566.27; found, 566.4 NMR (400 MHz, DMSO-d6) 8.36 (s, 1H), 7.65 (d, J= 4.2 Hz, 1H), 7.29 (d, J= 7.8 Hz, 2H), 7.09 (d, J=
8.1 Hz, 2H), 6.95 ¨ 6.79 (m, 2H), 6.09 (q, J= 6.9 Hz, 1H), 4.63 (s, 1H), 3.14 (s, 3H), 2.98 ¨2.87 (m, 3H), 2.58 (d, J= 2.6 Hz, 3H), 2.41 ¨2.17 (m, 3H), 2.10 ¨ 2.00 (m, 3H), 1.92 ¨ 1.77 (m, 3H), 1.75 ¨ 1.60 (m, 5H), 1.52 (d, J= 7.0 Hz, 3H), 1.46¨ 1.38 (m, 1H), 1.35 ¨ 1.22 (m, 2H).
Example 45 (3R)-3-cyclopenty1-3-(4-(7-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-b] indo1-1-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile /----\N-N
NC
\
\
NN

HN
\

..
9 /----\
NC N-N
N \
HO
Nr\ +
N-N 0 N ''= \
:
\
EDCI,DMAP,DCM
\ 0 [1.. -;:------N ri \
Synthesis of (3R)-3-cyclopenty1-3-(4-(7-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-b] indo1-1-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pynolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h]
indole -1-acetic acid (etodolac, 224 mg, 0.78 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 1) to give the title compound as a white solid, 0.28 g, 81.5% yield. MS (m/z):
[M+H] calcd for C34H371\1702, 576.30;
found,576.2 .41 NMR (400 MHz, DMSO-d6) .3 10.54 (s, 1H), 8.88 (d, J= 3.1 Hz, 2H), 8.42 (s, 1H), 8.09 (d, J=
4.2 Hz, 1H), 7.30 (d, J= 4.3 Hz, 1H), 7.24 (dd, J= 7.4, 1.5 Hz, 1H), 6.96 ¨6.87 (m, 2H), 4.66 ¨4.51 (m, 2H), 4.19 (dd, J= 14.5, 1.7 Hz, 1H), 3.88 (ddd, J= 11.8, 7.2, 5.0 Hz, 1H), 3.76 (dt, J= 11.1, 4.6 Hz, 1H), 3.30 ¨ 3.15 (m, 2H), 2.86 (q, J= 7.5 Hz, 2H), 2.64 ¨ 2.56 (m, 2H), 2.44 (q, J= 8.4 Hz, 1H), 2.18 (q, J= 7.2 Hz, 2H), 1.89 ¨
1.78 (m, 1H), 1.70¨ 1.41 (m, 4H), 1.41 ¨ 1.22 (m, 6H), 0.73 (t, J= 7.3 Hz, 3H).
Example 46 tert-butyl ((S)-2-(4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate 9\
H
N N

-S
N
H

C'µµ
NH
N

'N H EDCI, DMAP,DCM N N

k N
H
Synthesis of tert-butyl ((S)-2-(4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate N-methy1-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (163 mg, 0.65 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a white solid, 0.027 g, 9.4% yield. MS (m/z): [M+H] calcd for C28H38N605S, 571.26;
found,571.3 .1H NMR (400 MHz, DMSO-d6) .3 8.36 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 4.1 Hz, 1H), 7.56 - 7.45 (m, 3H), 7.29 (d, J = 7.7 Hz, 3H), 6.86 (d, J = 4.9 Hz, 2H), 4.63 (s, 1H), 3.14 (s, 3H), 2.94 (d, J =
6.2 Hz, 2H), 2.58 (d, J = 5.0 Hz, 3H), 2.03 (d, J = 12.7 Hz, 2H), 1.90- 1.79(m, 1H), 1.67 (d, J = 8.0 Hz, 4H), 1.39 (s, 9H), 1.32- 1.21 (m, 2H).
Example 47 2-(3-(4-(7-(2-((2, 3-Dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile .0 0' CN
NE.q) N-N
N \
N

NH

S
' N, 0' Nq..)CN
CN
0 OH 0 `
N-N EDCI, DMAP,DCM N \
kl\r N

N NH
Synthesis of 2-(3-(4-(7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-1-(ethylsulfonyl) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 371 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 289 mg, 1.2 mmol), and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 289 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate =
10: 1 to 1: 1) to give the title compound as a yellow solid, 0.25 g, 42% yield. MS (m/z): [M+H] calcd for C311-130N803S, 595.22; found, 595.2.1H NMR (400 MHz, DMSO-d6) .3 9.01 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 7.90 (d, J= 4.1 Hz, 1H), 7.42 (ddd, J= 12.4, 6.6, 3.0 Hz, 3H), 7.08 ¨6.99 (m, 2H), 6.94 (dd, J=
5.6, 3.2 Hz, 1H), 6.91 ¨6.75 (m, 2H), 4.62 (d, J= 9.1 Hz, 2H), 4.26 (d, J= 9.1 Hz, 2H), 3.71 (s, 2H), 3.24 (q, J=
7.3 Hz, 2H), 2.23 (s, 3H), 1.97 (s, 3H), 1.25 (t, J= 7.5 Hz, 3H).
Example 48 4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate 1\1µµ 1\11-r0N

EDO DMAp, N
LL- OH
DCM,DMF
NSOCN
¨

Synthesis of 4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) .. (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 170 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 1) to give the title compound as a white solid, 0.107 g, 38.6% yield. MS (m/z): [M+H] calcd for C31H34N604, 555.26; found, 555.3.1H NMR (400 MHz, Chloroform-d) .3 8.31 (d, J= 4.1 Hz, 1H), 7.69 ¨ 7.49 (m, 3H), 7.32 (dt, J= 8.6, 2.5 Hz, 1H), 7.20¨ 7.02 (m, 3H), 6.47 (d, J= 3.8 Hz, 1H), 6.22¨ 6.06 (m, 2H), 5.10 (d, J= 8.2 Hz, 1H), 4.06 (dd, J=
13.4, 4.5 Hz, 1H), 3.91 (s, 3H), 3.88 ¨3.66 (m, 2H), 3.66 ¨ 3.44 (m, 4H), 3.34 (d, J= 11.5 Hz, 3H), 2.49 (dt, J=
20.2, 6.2 Hz, 1H), 1.99¨ 1.83 (m, 1H), 1.81 ¨ 1.65 (m, 1H), 1.54 (d, J= 7.1 Hz, 3H), 1.08 (dd, J= 9.5, 7.0 Hz, 3H).
Example 49 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate 1\1µµ 1-rCN

N
m N

IrCN N0 .
OH EDOLDMAP, N N
\--0 OH DCM,DMF

Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 191 mg, 1.5 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a white solid, 0.153 g, 52.9% yield. MS (m/z): [M+H] calcd for C33H34N604, 579.26; found, 579.3.1H NMR (400 MHz, Chloroform-d) .3 8.29 (d, J= 4.5 Hz, 1H), 7.78 ¨ 7.69 (m, 2H), 7.68 ¨ 7.54 (m, 3H), 7.51 ¨7.42 (m, 3H), 7.36 (td, J= 7.6, 2.1 Hz, 1H), 7.10¨ 7.01 (m, 1H), 6.52 ¨
6.42 (m, 1H), 6.21 ¨ 6.10 (m, 2H), 5.10 (dt, J= 9.0, 4.7 Hz, 1H), 4.09 ¨3.72 (m, 3H), 3.67¨ 3.43 (m, 4H), 3.35 (dd, J= 13.1, 4.9 Hz, 3H), 2.56 ¨
2.41 (m, 1H), 2.00¨ 1.85 (m, 1H), 1.80¨ 1.71 (m, 1H), 1.50 (d, J= 7.2 Hz, 3H), 1.07 (dd, J= 10.5, 7.1 Hz, 3H).
Example 50 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1'-bipheny11-4-y1) propanoate N"
NCN
N
N

NSSNCN
OH

b'r EDC DCMI,DDMAP, N N
0 e¨N
,MF
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 183 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
1) to give the title compound as a white solid, 0.083 g, 29.2% yield. MS (m/z): [M+H] calcd for C32H33FN603, 569.26; found, 569.3.1H NMR (400 MHz, Chloroform-d) .3 8.31 (d, J = 2.2 Hz, 1H), 7.53 ¨ 7.47 (m, 2H), 7.46 ¨
7.40 (m, 2H), 7.39 ¨ 7.28 (m, 2H), 7.16 ¨ 7.09 (m, 1H), 7.08 ¨6.85 (m, 2H), 6.51 (q, J= 3.3 Hz, 1H), 6.23 ¨6.10 (m, 2H), 5.09 (s, 1H), 4.08 ¨3.69 (m, 4H), 3.67¨ 3.33 (m, 6H), 2.55 ¨2.37 (m, 1H), 1.99 ¨1.81 (m, 1H), 1.80¨
1.71 (m, 1H), 1.49 (dd, J = 7.3, 2.6 Hz, 3H), 1.10¨ 1.00 (m, 3H).
Example 51 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate N" N 1-rCN
N
N

CI

EDCI, DMAp, N
N CI
OH DCM,DMF

CI
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2, 6-dichloroanilino) phenylacetic acid (diclofenac, 222 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
1) to give the title compound as a white solid, 0.106 g, 34.2% yield. MS (m/z): [M+H] calcd for C311-131C12N703, 620.19; found,620.3.11-1 NMR
(400 MHz, Chloroform-d) .3 8.34 (d, J= 8.2 Hz, 1H), 7.32 (dd, J= 8.1, 1.8 Hz, 2H), 7.18 (dd, J = 7.5, 1.7 Hz, 1H), 7.12 (dd, J= 9.3, 5.7 Hz, 2H), 6.96 (dt, J= 15.1, 7.8 Hz, 2H), 6.64 (d, J= 9.4 Hz, 1H), 6.53 (dq, J= 7.6, 3.3 Hz, 2H), 6.23 (d, J= 3.9 Hz, 2H), 5.13 (s, 1H), 4.10 ¨ 3.56 (m, 6H), 3.52 (t, J=
7.6 Hz, 2H), 3.39 (s, 1H), 3.34 (s, 2H), 2.50 (ddd, J= 19.4, 9.7, 4.0 Hz, 1H), 1.99 ¨ 1.83 (m, 1H), 1.76 (dq, J= 17.7, 3.9, 3.2 Hz, 1H), 1.09 (dd, J= 13.9, 7.1 Hz, 3H).
Example 52 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-phenoxyphenyl) propanoate Th\rs N \
N7 N\
o N'N' NCN
H _F tiith 0 H EDCLDMAP, 0 DCM,DMF
\--OH 0 *
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-phenoxyphenyl) propanoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 182 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
1) to give the title compound as a white solid, 0.13 g, 45.9% yield. MS (m/z): [M+H] calcd for C32H34N604, 567.26; found, 567.3.1H NMR (400 MHz, Chloroform-d) .3 8.32 (d, J = 6.6 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.20 (td, J = 7.9, 2.2 Hz, 1H), 7.13 ¨
7.05 (m, 2H), 6.96 (d, J= 7.2 Hz, 3H), 6.92 ¨ 6.87 (m, 1H), 6.83 (d, J= 8.2 Hz, 1H), 6.51 (t, J= 3.1 Hz, 1H), 6.21 ¨6.07 (m, 2H), 5.11 (dp, J= 9.4, 4.8, 4.4 Hz, 1H), 4.10 ¨ 3.65 (m, 3H), 3.63 ¨3.49 (m, 3H), 3.47- 3.41 (m, 1H), 3.40 ¨ 3.31 (m, 3H), 2.48 (dp, J= 25.5, 6.1 Hz, 1H), 1.94 (dt, J= 9.4, 4.6 Hz, 1H), 1.80¨ 1.66 (m, 1H), 1.45 (d, J
= 7.2 Hz, 3H), 1.08 (dd, J= 12.3, 7.1 Hz, 3H).
Example 53 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate Ns, L'IC01\1 N \
kNr N\
(Di s'N"

EDCI, DMAP, DCM,DMF 0 Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin .. -4-y1) .. (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 185 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
1) to give the title compound as a white solid, 0.08 g, 28% yield. MS (m/z): [M+H] calcd for C32H38N604, 571.30;
found, 571.3.1H NMR (400 MHz, Chloroform-d) .3 8.34¨ 8.27 (m, 1H), 7.11 (if, J= 9.3, 7.5, 3.4 Hz, 3H), 7.04 (dt, J = 8.3, 2.9 Hz, 2H), 6.51 (s, 1H), 6.17 (dd, J= 10.5, 4.6 Hz, 1H), 6.10 (dt, J= 10.6, 2.8 Hz, 1H), 5.12 (qd, J= 8.6, 5.0 Hz, 1H), 4.11 ¨3.57 (m, 5H), 3.50 (q, J= 9.1, 7.3 Hz, 3H), 3.40 (d, J= 2.2 Hz, 1H), 3.14 ¨ 3.02 (m, 1H), 2.49 (ddd, J= 23.3, 11.0, 4.9 Hz, 2H), 2.33 (dd, J= 17.7, 8.4 Hz, 2H), 2.16 ¨ 2.01 (m, 2H), 1.95 (tdd, J=

11.1, 5.8, 2.8 Hz, 2H), 1.83 ¨ 1.60 (m, 3H), 1.58¨ 1.47 (m, 1H), 1.44 (dd, J= 7.2, 1.8 Hz, 3H), 1.08 (t, J= 7.2 Hz, 3H).
Example 54 (3R)-3-cyclopenty1-3-(4-(7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyr azol-1-y1) propanenitrile NCi¨\N¨N
N

CA 03224493 2023¨ 12¨ 28 N N-N NC N-N
C

H EDCI,DMAP,DCM
NN''= \ 0 \
N N

Synthesis of (3R)-3-cyclopenty1-3-(4-(7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 189 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 3: 1) to give the title compound as a white solid, 0.2 g, 62.8% yield. MS (m/z): [M+H] calcd for C32H30N602, 531.24;
found,531.2.11-1 NMR (400 MHz, DMSO-d6) .3 8.86 (d, J= 13.5 Hz, 2H), 8.41 (s, 1H), 8.09 (d, J= 4.2 Hz, 1H), 7.40 ¨ 7.26 (m, 4H), 7.20 ¨ 7.09 (m, 2H), 7.07 (t, J= 2.1 Hz, 1H), 6.91 (d, J= 8.0 Hz, 2H), 6.84 (dd, J= 8.1, 2.5 Hz, 1H), 5.96 (q, J= 6.9 Hz, 1H), 4.54 (td, J= 9.6, 4.2 Hz, 1H), 3.29 ¨ 3.15 (m, 2H), 2.42 (p, J= 8.5 Hz, 1H), 1.82 (dtd, J= 12.1, 7.4, 3.8 Hz, 1H), 1.66¨ 1.40 (m, 7H), 1.37 ¨ 1.18 (m, 3H).
Example 55 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate -,Ns=
NvcN
N \
kN

CI

'IrCN

NNNCN )/Xl>1 0 EDCI DMAP, +
\-_OH DCM DMF 0 CI
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) -- (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate =
2: 1 to 1: 1) to give the title compound as a light yellow solid, 0.036 g, 10.5% yield. MS (m/z): [M+H] calcd for C36H36C1N705, 682.25;
found,682.3.1H NMR (400 MHz, Chloroform-d) .3 8.32 (s, 1H), 7.68 ¨ 7.59 (m, 2H), 7.51 ¨ 7.43 (m, 2H), 7.09 (d, J= 3.8 Hz, 1H), 6.91 ¨ 6.78 (m, 2H), 6.65 (dd, J= 9.0, 2.4 Hz, 1H), 6.50 (dd, J= 8.2, 3.8 Hz, 1H), 6.19 (s, 2H), 5.19 ¨ 5.09 (m, 1H), 4.10 ¨ 3.73 (m, 6H), 3.70 ¨ 3.56 (m, 4H), 3.55 ¨ 3.45 (m, 3H), 3.39 (s, 1H), 2.58 ¨2.42 (m, 1H), 2.29 (d, J= 10.3 Hz, 3H), 2.03 ¨ 1.85 (m, 1H), 1.81 ¨ 1.73 (m, 1H), 1.09 (dd, J= 11.4, 7.1 Hz, 3H).
Example 56 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-acetoxybenzoate N \
kN N
o/

Ns NCN
-1r.CN
1\el N N 0 DEAD,Ph3P,DMF,DCM N

N \--OH OH

Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-acetoxybenzoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-acetoxybenzoic acid (aspirin, 135 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
1) to give the title compound as a light yellow solid, 0.178 g, 70.6% yield. MS (m/z): [M+H] calcd for C26H28N605, 505.21; found,505.3.11-1 NMR
(400 MHz, Chloroform-d) .3 8.34 (d, J= 6.5 Hz, 1H), 8.01 (d, J= 7.9 Hz, 1H), 7.60 ¨ 7.50 (m, 1H), 7.31 ¨7.18 (m, 2H), 7.07 (d, J= 8.1 Hz, 1H), 6.57 (d, J= 3.8 Hz, 1H), 6.37 (d, J= 2.6 Hz, 2H), 5.12 (if, J= 8.3, 4.6 Hz, 1H), 4.25 ¨ 3.98 (m, 1H), 3.80 (ddt, J= 13.2, 8.8, 4.7 Hz, 1H), 3.62 ¨ 3.50 (m, 3H), 3.37 (d, J= 15.2 Hz, 3H), 2.49 (dp, J= 24.6, 6.0 Hz, 1H), 2.25 (d, J= 12.7 Hz, 3H), 1.93 (dtt, J= 17.8, 9.0, 4.5 Hz, 2H), 1.74 (dtt, J= 17.9, 7.6, 3.5 Hz, 1H), 1.08 (dd, J= 13.2, 7.0 Hz, 3H).
Example 57 (R)-3-(4-(7-(2-((3-chloro-2-methylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyra zol-1-y1)-3-cyclopentylpropanenitrile NCNN

NH
CI

NC N-N
NCi-\N-N 0 + OH
EDCI, DMAP,DCM
CI N
RD

N
* NH
* CI
Synthesis of (R)-3-(4-(7-(2-((3-chloro-2-methylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 306 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 261 mg, 1 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 289 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 1) to give the title compound as a yellow solid, 0.26 g, 47.3% yield. MS (m/z): [M+H] calcd for C31H28C1N70, 550.20; found, 550.1.1H NMR (400 MHz, DMSO-d6) .3 8.87 (s, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 7.80 (d, J= 4.1 Hz, 1H), 7.49 (t, J= 7.7 Hz, 2H), 7.27 (d, J= 4.1 Hz, 1H), 7.12¨ 7.00 (m, 3H), 7.00 ¨ 6.91 (m, 2H), 4.55 (td, J= 9.6, 4.2 Hz, 1H), 3.29 ¨
3.17 (m, 2H), 2.43 (p, J= 8.5 Hz, 1H), 2.02 (s, 3H), 1.83 (dtd, J= 11.9, 7.3, 3.9 Hz, 1H), 1.69¨ 1.42 (m, 4H), 1.41 ¨ 1.27 (m, 2H), 1.23 (td, J= 9.4, 8.7, 2.9 Hz, 1H).
Example 58 N-(4-(2-(4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide 9\
HN
H 'N

C).µ
H
õNõ- HO s [ EDCI, DMAI:,DCM
NO

N
N

Synthesis of N-(4-(2-(4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide N-Methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 126 mg, 0.65 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
2: 1 to 0: 1) to give the title compound as a white solid, 0.017 g, 6.6% yield. MS (m/z): [M+H] calcd for C25H32N6045, 513.22;
found,513.3.11-1 NMR (400 MHz, DMSO-d6) .3 9.90 (s, 1H), 8.37 (s, 1H), 7.68 (d, J= 4.2 Hz, 1H), 7.51 (d, J= 8.4 Hz, 2H), 7.25 (d, J= 8.4 Hz, 2H), 6.88 (d, J= 4.9 Hz, 2H), 4.81 (s, 2H), 4.67 (s, 1H), 3.18 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.59 (d, J= 4.9 Hz, 3H), 2.03 (s, 5H), 1.94¨ 1.80 (m, 1H), 1.70 (dd, J= 8.6, 3.4 Hz, 4H), 1.37¨ 1.26 (m, 2H).
Example 59 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate NIµµ 1\11rCN

NH

NNCN
N

0 EDCI,DMAP,DMF,DCM., \--OH
NH
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (171 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 145 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in a mixed solvent of dichloromethane (8.5 mL) and N, N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.154 g, yield 59.5%. MS (m/z):
[M+H] calcd for C27H3IN704, 518.24; found, 518.3.1H NMR (400 MHz, Chloroform-d) .3 8.33 (d, J= 4.2 Hz, 1H), 7.71 (d, J = 29.0 Hz, 1H), 7.40 (d, J= 8.1 Hz, 2H), 7.10 (dt, J= 13.1, 4.8 Hz, 3H), 6.51 (dd, J= 8.4, 3.9 Hz, 1H), 6.16 (s, 2H), 5.10 (if, J=
9.2, 4.4 Hz, 1H), 4.10 ¨ 3.75 (m, 2H), 3.63 ¨3.44 (m, 6H), 3.36 (d, J= 18.1 Hz, 3H), 2.55 ¨2.44 (m, 1H), 2.00 (s, 3H), 1.97¨ 1.87 (m, 1H), 1.83 - 1.67 (m, 1H), 1.09 (t, J= 7.5 Hz, 3H).
Example 60 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) (S)-2-(4-isobutylphenyl) propanoate .0 s *CN
N-N
N \
N\
o -S' 0' = CN
-S' 0' 'N CN 0' CN 0' 'N CN

SEMCI, DIPEA DCM Nqj TFA DCM 1-1) N-N N-N N-N N \
N
N
EDCI, DMAP,DCM
N \ N \ N \o N H
o) HO
Si¨
/
First step: synthesis of 2-(1-(ethylsulfony1)-3-(4-(7-02-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitrile (baricitinib, 7420 mg, 20 mmol) and N, N-diisopropylethyl amine (3.12 g, 24 mmol) were dissolved in dichloromethane (200 mL) under nitrogen protection. After stirring at room temperature for half an hour, (2-(chloromethoxy) ethyl) timethylsilane (4 g, 24 mmol) was added, stirring was continued at room temperature overnight. The solvent was evaporated under reduced pressure to give the crude product. The crude product was further isolated by silica gel column chromatography to give the title compound as a white solid, 5 g, 49%
yield. MS (m/z): [M+H]+ calcd for C22H311\1703SSi, 502.20; found, 502.3.
Step 2: synthesis of 2-(1-(ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile Trifluoroacetic acid (6.44 g, 56.5 mmol) was slowly added dropwise to a solution of 2-(1-(ethylsulfony1)-3-(4-(7((2-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (5 g, 11.3 mmol) in dichloromethane (100 mL) under nitrogen in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 24 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0 C to adjust the pH to 8. Then, the mixture was poured into a separation funnel and separated. The organic layer was washed with a saturated salt water solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title product 3.5 g, 90%
yield. MS (m/z): [M+H] calcd for Ci7HoN703S,402.13; found, 402.3.
Step 3: synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) (S)-2-(4-isobutylphenyl) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid((S)-(+)-ibuprofen, 123.6 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a white solid, 0.025 g, 8.4% yield. MS (m/z): [M+H] calcd for C30H35N7045, 590.25, found 590.3.1H NMR
(400 MHz, DMSO-d6) 8.95 (s, 1H), 8.77 (s, 1H), 8.48 (s, 1H), 7.70 (d, J= 3.8 Hz, 1H), 7.16 (d, J=
3.8 Hz, 1H), 7.06 (d, J= 7.8 Hz, 2H), 6.96 (d, J= 7.8 Hz, 2H), 6.25 (d, J= 3.2 Hz, 2H), 4.60 (d, J= 9.1 Hz, 2H), 4.25 (d, J= 9.1 Hz, 2H), 3.76 (q, J=
7.0 Hz, 1H), 3.69 (s, 2H), 3.24 (q, J= 7.3 Hz, 2H), 2.32 (d, J= 7.1 Hz, 2H), 1.71 (hept, J= 6.7 Hz, 1H), 1.34 (d, J
= 7.1 Hz, 3H), 1.26 (d, J= 7.4 Hz, 3H), 0.77 (d, J= 6.5 Hz, 6H).
Example 61 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) (S)-2-(6-methoxynaphthalen-2-y1) propanoate .0 OSs CN
N-N
N \
kN N\
o It, CN
CN
Nqj -S' N-N
N-N HO EDCI, DMAP,DCM
N \
0 11-Nr N
N \
k-Nr N 0>
HO) Ilri. 0 Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) (S)-2-(6-methoxynaphthalen-2-y1) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (401 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 276 mg, 1.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1 to 1: 1) to give the title compound as a white solid, 0.31 g, 50.5% yield. MS (m/z): [M+H] calcd for C3iH3IN705S, 614.21; found,614.3.1H NMR
(400 MHz, DMSO-d6) .3 8.94 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 7.72 (d, J = 3.8 Hz, 1H), 7.65 (dd, J = 10.9, 8.8 Hz, 2H), 7.56 (d, J = 1.9 Hz, 1H), 7.29 (dd, J= 8.5, 1.9 Hz, 1H), 7.22 (d, J= 2.6 Hz, 1H), 7.16 (d, J =
3.8 Hz, 1H), 7.08 (dd, J = 8.9, 2.6 Hz, 1H), 6.28 (s, 2H), 4.61 (d, J= 9.1 Hz, 2H), 4.26 (d, J= 9.1 Hz, 2H), 3.94 (q, J= 7.0 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.24 (q, J= 7.3 Hz, 2H), 1.44 (d, J= 7.1 Hz, 3H), 1.26 (t, J=
7.4 Hz, 3H).
Example 62 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate .0 -s-o- = CN
Niq) N-N
\
N \
kN N\

-S' .0 0' s CN
-S' NRI
0' ' CN N¨N

N¨N OH EDCI, DMAP,DCM
\ +
N 0 N \
N 0) --N' ) 0 HO

Synthesis of 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitile (401 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol) 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 305 mg, 1.2 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1 to 1: 1) to give the title compound as a white solid, 0.43 g, 67.5% yield. MS (m/z):
[M+H] calcd for C33H3IN7055, 638.21; found,638.2.1H NMR (400 MHz, DMSO-d6) .3 8.95 (s, 1H), 8.75 (s, 1H), 8.48 (s, 1H), 7.71 (d, J= 3.8 Hz, 1H), 7.69¨ 7.62 (m, 3H), 7.59 (t, J= 1.8 Hz, 1H), 7.57¨ 7.49 (m, 4H), 7.43 (t, J= 7.6 Hz, 1H), 7.17 (d, J= 3.8 Hz, 1H), 6.28 (d, J= 4.4 Hz, 2H), 4.62 (d, J= 9.1 Hz, 2H), 4.27 (d, J= 9.1 Hz, 2H), 3.99 (q, J= 7.1 Hz, 1H), 3.71 (s, 2H), 3.25 (q, J= 7.3 Hz, 2H), 1.41 (d, J= 7.1 Hz, 3H), 1.26 (t, J= 7.3 Hz, 3H).
Example 63 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indol -1-y1) acetate NSNCN
NSNCN

HN

HO
cN 0 EDCI,DMAP,DMF,DCM
0 \--0 \--OH 0 HN
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 241, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b]
indol -1-y1) acetate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (171 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole -1-acetic acid (etodolac, 216 mg, 0.75 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5mL) and dimethylformamide (0.3mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.18 g, 58.9% yield. MS (m/z): [M+H] calcd for C34H4IN704, 612.32; found, 612.3.1H NMR (400 MHz, Chloroform-d) .3 8.97 (d, J= 13.6 Hz, 1H), 8.31 (d, J=
8.1 Hz, 1H), 7.33 (d, J= 7.6 Hz, 1H), 7.10¨ 7.02 (m, 2H), 7.00 (d, J= 7.3 Hz, 1H), 6.51 (d, J= 4.1 Hz, 1H), 6.17 (dtd, J= 15.9, 10.7, 4.1 Hz, 2H), 5.10 (dp, J= 14.0, 4.6 Hz, 1H), 4.09 ¨3.70 (m, 5H), 3.60¨ 3.47 (m, 3H), 3.35 (d, J= 14.9 Hz, 3H), 3.02 (d, J= 16.2 Hz, 1H), 2.87 (ddd, J= 16.8, 12.9, 5.8 Hz, 3H), 2.68 (dt, J= 15.4, 4.3 Hz, 1H), 2.56 ¨ 2.41 (m, 1H), 2.07 (dt, J= 14.3, 6.8 Hz, 1H), 1.98 (s, 2H), 1.90 (d, J= 24.6 Hz, 3H), 1.79¨ 1.65 (m, 1H), 1.37 (ddd, J= 10.0, 6.5, 2.4 Hz, 3H), 1.06 (dt, J= 13.8, 6.3 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H).
Example 64 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate N" NCN
\--0 FI
N

N
1\lsµ r\jIrCN

+
EDCI,DMAP,DMF,DCM
OH ___________________________________________ OH
H
=0 Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (189 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in a mixed solvent of dichloromethane (8.5 mL) and N, N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) CA 03224493 2023¨ 12¨ 28 to give the title compound as a white solid, 0.148 g, 51.4% yield. MS (m/z):
[M+H] calcd for C30H37N705, 576.29; found, 576.3.1H NMR (400 MHz, Chloroform-d) .3 8.28 (d, J= 9.3 Hz, 1H), 7.25 (d, J= 6.9 Hz, 5H), 7.07 (dd, J= 16.0, 3.9 Hz, 1H), 6.51 (dd, J= 7.1, 3.7 Hz, 1H), 6.23 ¨6.14 (m, 2H), 5.49 (d, J= 7.5 Hz, 1H), 5.29 (d, J
= 7.5 Hz, 1H), 5.11 (dt, J= 9.7, 4.5 Hz, 1H), 4.13 ¨3.76 (m, 2H), 3.63 ¨3.46 (m, 4H), 3.36 (d, J= 17.3 Hz, 3H), 2.49 (if, J= 13.9, 6.0 Hz, 1H), 1.87 (dd, J= 9.5, 4.6 Hz, 1H), 1.82¨ 1.67 (m, 1H), 1.39 (s, 9H), 1.08 (dd, J= 13.5, 7.1 Hz, 3H).
Example 65 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-(1-oxoisoindo1-2-y1)) phenyl) butanoate 1\1"

N

OH rCN

N CN
N N
\--0 0 EDCI,DMAP,DMF,DCM

NN
\--OH

Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-(1-oxoisoindo1-2-y1)) phenyl) butanoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (20 mg, 0.058 mmol), 4-dimethylamino pyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 26 mg, 0.09 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 17 mg, 0.09 mmol) were dissolved in a mixed solvent of dichloromethane (0.5mL) and N, N-dimethylformamide (0.05mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.012 g, 33.4% yield. MS (m/z):
[M+H] calcd for C35H37N704, 620.29; found,620.3 .1H NMR (400 MHz, Chloroform-d) .3 8.30 (d, J= 8.7 Hz, 1H), 7.90 (d, J= 7.5 Hz, 1H), 7.80 ¨7.69 (m, 2H), 7.59 (t, J= 7.5 Hz, 1H), 7.51 (d, J= 8.4 Hz, 2H), 7.33 ¨7.22 (m, 2H), 7.14 ¨ 7.06 (m, 1H), 6.53 ¨
6.45 (m, 1H), 6.15 (dt, J= 18.9, 10.9 Hz, 2H), 5.08 (s, 1H), 4.82 (s, 2H), 4.05 (d, J= 13.5 Hz, 1H), 3.92 ¨ 3.66 (m, 2H), 3.53 (q, J= 6.6, 5.1 Hz, 3H), 3.37 ¨ 3.27 (m, 3H), 2.54 ¨ 2.40 (m, 1H), 2.07 (dq, J= 14.1, 7.3 Hz, 2H), 1.93 (s, 1H), 1.76 (if, J= 19.7, 8.8 Hz, 2H), 1.06 (s, 3H), 0.82 (s, 3H).
Example 66 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-((3-chloro-2-methylphenyl) amino) benzoate N

HN
NSNCN
CI

N'ircN CI
0 Al NH OH EDCI,DMAP,DMF,DCM
N
N
HN
Cit CI
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-((3-chloro-2-methylphenyl) amino) benzoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (200 mg, 0.58 mmol), 4-dimethylamino pyridine (DMAP, 35 mg, 0.29 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 230 mg, 0.88 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 168 mg, 0.88 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N, N-dimethylformamide (0.2 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a yellow solid,0.145 g, 42.7% yield. MS (m/z):
[M+H] calcd for C31H32C1N703, 586.23; found, 586.3.1H NMR (400 MHz, Chloroform-d) .3 9.20 (s, 1H), 8.37 (d, J= 7.1 Hz, 1H), 7.95 (dd, J= 8.2, 1.7 Hz, 1H), 7.30 ¨ 7.17 (m, 4H), 7.12 (t, J= 7.9 Hz, 1H), 6.75 (d, J= 8.5 Hz, 1H), 6.65 (t, J= 7.6 Hz, 1H), 6.60 ¨

6.55 (m, 1H), 6.42 (d, J= 3.3 Hz, 2H), 5.13 (q, J= 6.0, 5.5 Hz, 1H), 4.12 ¨3.75 (m, 2H), 3.64¨ 3.56 (m, 1H), 3.53 ¨ 3.46 (m, 2H), 3.38 (d, J= 16.8 Hz, 3H), 2.58 ¨2.44 (m, 1H), 2.32 (s, 3H), 1.97 - 1.82 (m, 2H), 1.81 ¨ 1.68 (m, 1H), 1.08 (dd, J= 12.9, 7.0 Hz, 3H).
Example 67 (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) benzoate N"

N

HN
HO
`Nr"---Nly^cN o 110 o 0 HN , õ EDCI DMAP DMF DCM
\--OH 0 HN
Synthesis of (4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) benzoate 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 181 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N, N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a yellow solid, 0.012 g, 45.6% yield. MS (m/z):
[M+H] calcd for C32H35N703, 566.28; found, 566.3.1H NMR (400 MHz, Chloroform-d) .3 9.14 (s, 1H), 8.37 (d, J= 7.1 Hz, 1H), 7.93 (dd, J= 8.1, 1.7 Hz, 1H), 7.29 (dd, J= 15.0, 3.7 Hz, 1H), 7.25 ¨ 7.16 (m, 1H), 7.16 ¨ 7.06 (m, 2H), 7.03 (d, J= 6.8 Hz, 1H), 6.68 (d, J= 8.6 Hz, 1H), 6.63 ¨6.53 (m, 2H), 6.41 (d, J= 3.0 Hz, 2H), 5.12 (dt, J= 9.7, 4.7 Hz, 1H), 4.05 (dd, J=
13.2, 4.4 Hz, 1H), 3.78 (ddd, J= 15.8, 13.2, 8.1 Hz, 1H), 3.58 (td, J= 11.3, 10.3, 5.0 Hz, 1H), 3.54 ¨ 3.47 (m, 2H), 3.37 (d, J= 15.3 Hz, 3H), 2.57 ¨ 2.41 (m, 1H), 2.33 (s, 3H), 2.17 (s, 3H), 1.99 (s, 1H), 1.97¨ 1.84 (m, 1H), 1.72 (dtd, J= 32.5, 6.4, 3.6 Hz, 1H), 1.07 (dd, J= 13.3, 7.0 Hz, 3H).
Example 68 N-methyl-1-((trans)-4-(methyl (7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide 9\
-S
N \n`
H
kNN

H
H ,7'10 0 OH EDCI,DMAP,DCM
=kr, N
0 rt, 16h r\

Synthesis of N-methyl-1-((trans)-4-(methyl (7-(2-(3-phenoxyphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide N-methy1-1-((trans)-4-(methyl (7H-pynolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 168 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 158 mg, 0.65 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 5:3) to give the title compound as a white solid, 0.18 g, 64.1% yield. MS (m/z): [M+H]
calcd for C301-135N5045, 562.24;
found, 562.4.1H NMR (400 MHz, DMSO-d6) .3 8.26 (s, 1H), 7.65 (d, J= 4.2 Hz, 1H), 7.40 ¨ 7.33 (m, 2H), 7.29 (t, J= 7.9 Hz, 1H), 7.18 ¨ 7.11 (m, 2H), 7.05 (t, J= 2.1 Hz, 1H), 6.98 ¨ 6.90 (m, 2H), 6.90 ¨ 6.78 (m, 3H), 6.06 (q, J
= 6.9 Hz, 1H), 4.64 (s, 1H), 3.15 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.60 (d, J= 5.0 Hz, 3H), 2.10 ¨ 2.02 (m, 2H), 1.92¨ 1.77 (m, 1H), 1.70 (if, J= 8.2, 3.1 Hz, 4H), 1.53 (d, J= 7.0 Hz, 3H), 1.29 (d, J= 12.9 Hz, 2H).
Example 69 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoate .0 .S' 0' s CN
Niq) N¨N
\
N
N \
k - N

F
,.0 -S' ,-0 Nilq) N¨N
-S' 0' ` \

L--- + OH
N¨N EDCI DMAP
y:0 0 _______ DCM,DMF
F
kr\i' N 0 HO) F
Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(2-fluoro-[1, 1'-bipheny11-4-y1) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 146 mg, 0.6 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and N, N-dimethylformamide (1 mL) and stirred at room temperature for 18 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
5: 1 to 1: 2) to give the title compound as a white solid, 0.27 g, 86.1% yield. MS (m/z): [M+H] calcd for C32H30FN704S, 628.21;
found,628.3.1H NMR (400 MHz, DMSO-d6) .3 8.95 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.75 (d, J = 3.8 Hz, 1H), 7.50¨ 7.41 (m, 4H), 7.40 ¨7.32 (m, 2H), 7.19 (d, J= 3.8 Hz, 1H), 7.17¨ 7.08 (m, 2H), 6.37 ¨ 6.24 (m, 2H), 4.60 (d, J= 9.1 Hz, 2H), 4.25 (d, J= 9.1 Hz, 2H), 3.93 (q, J= 7.0 Hz, 1H), 3.69 (s, 2H), 3.23 (q, J= 7.3 Hz, 2H), 1.40 (d, J= 7.1 Hz, 3H), 1.25 (t, J= 7.2 Hz, 3H).
Example 70 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]

pyrimidin -7-y1) 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate .0 -s\-0' CN
NLq) N-N
\
N
N \
kNr N\
o2 CI
HN

CI
.0 -S' ,0 0' s CN
I\Llq) .S' CN
NLq, j N-N
\
N
N-N CI EDCI, DMAP, \ + HO0 _____________ ,..
N
HN . DCM,DMF N ''''= \
N '-- \ CI N 0) kN- N CI
HC? 0 HN ip CI
Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(2, 6-dichloroanilino) phenylacetic acid (diclofenac, 148 mg, 0.5 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and N, N-dimethylformamide (2 mL) and stirred at room temperature for 18 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
10: 1 to 1: 2) to give the title compound as a white solid, 0.07 g, 20.6% yield. MS (m/z): [M+H] calcd for C311-128C12N8045, 679.13;
found,679.1.1H NMR (400 MHz, DMSO-d6) .3 8.96 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 7.76 (d, J= 3.8 Hz, 1H), 7.49 (d, J= 8.1 Hz, 2H), 7.24 ¨ 7.12 (m, 3H), 7.04 (td, J= 7.7, 1.6 Hz, 1H), 6.92 (s, 1H), 6.81 (td, J= 7.4, 1.2 Hz, 1H), 6.32 (s, 2H), 6.22 (d, J= 8.0 Hz, 1H), 4.61 (d, J= 9.1 Hz, 2H), 4.26 (d, J= 9.1 Hz, 2H), 3.86 (s, 2H), 3.70 (s, 2H), 3.24 (q, J= 7.4 Hz, 2H), 1.26 (t, J= 7.4 Hz, 3H).
Example 71 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(3-phenoxyphenyl) propanoate - Ss' 0' CN
14) N-N
\
N
N \
k - N

o .0 .s, ..0 O'' CN
) -S' 0' `Nit ICN 4 'N \
N-N 0 OH + 1101 EDCLDMAPDCM
\ _______________________________________ ..
kN
N '''. \ \-0 kN

HO( o Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(3-phenoxyphenyl) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 1345 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a white solid, 0.22 g, 70.4% yield. MS (m/z): [M+H] calcd for C32H311\17055, 626.21; found,626.1.11-1 NMR (400 MHz, DMSO-d6) .3 8.96 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.71 (d, J = 3.8 Hz, 1H), 7.39 ¨
7.30 (m, 2H), 7.24 (t, J = 7.9 Hz, 1H), 7.19 (d, J= 3.8 Hz, 1H), 7.11 (t, J= 7.4 Hz, 1H), 6.97 (d, J= 7.7 Hz, 1H), 6.90 (d, J= 8.0 Hz, 2H), 6.85 (t, J= 2.1 Hz, 1H), 6.79 (dd, J= 8.1, 2.5 Hz, 1H), 6.27 (d, J= 4.3 Hz, 2H), 4.61 (d, J=
9.1 Hz, 2H), 4.26 (d, J = 9.1 Hz, 2H), 3.84 (q, J= 7.1 Hz, 1H), 3.70 (s, 2H), 3.24 (q, J= 7.3 Hz, 2H), 1.35 (d, J=
7.1 Hz, 3H), 1.25 (t, J= 7.2 Hz, 3H).
Example 72 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate .0 .S' 0' s CN
N¨N
\
\
N \
k , N

.0 0- = CN
No(' .S' 0' ' CN \
4) N
N-N 0 0 EDCI, DMAP,Dcm Nkri----- \

HO) Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 148 mg, 06 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a white solid, 0.26 g, 82.6% yield. MS (m/z): [M+H] calcd for C32H35N705S, 630.24; found,630.1.11-1 NMR (400 MHz, DMSO-d6) .3 8.96 (s, 1H), 8.78 (d, J= 1.6 Hz, 1H), 8.49 (s, 1H), 7.71 (d, J= 3.8 Hz, 1H), 7.17 (d, J= 3.8 Hz, 1H), 7.04 (ddd, J
= 25.3, 8.1, 2.3 Hz, 4H), 6.26 (d, J= 4.2 Hz, 2H), 4.60 (d, J= 9.1 Hz, 2H), 4.25 (d, J= 9.1 Hz, 2H), 3.77 (q, J=
7.1 Hz, 1H), 3.69 (s, 2H), 3.24 (q, J= 7.3 Hz, 2H), 2.87 (dd, J= 13.3, 3.7 Hz, 1H), 2.40 ¨ 2.15 (m, 3H), 2.04 (dd, J= 10.2, 8.5 Hz, 1H), 1.80 (d, J= 12.9 Hz, 2H), 1.70 -156 (m, 1H), 1.44¨ 1.31 (m, 4H), 1.28 ¨ 1.23 (m, 3H).
Example 73 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]

pyrimidin -7-y1) 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate - s-o- ' CN
N-N
\
N
N \
N N\
o2 /
CI
.0 1,4 j -S' OH
0' ' CN N-N
N

N-N -, \ EDCI, DMAP,DCM
NY----\'''' \ +
N
0 N '- \
kN7 N
c?

HO ¨

/
CI
Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 214 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a yellow solid, 0.26 g, 75.6% yield. MS (m/z): [M+H] calcd for C36H33C1N806S, 741.19; found,741.1.1H
NMR (400 MHz, DMSO-d6) .3 8.98 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 7.76 (d, J= 3.8 Hz, 1H), 7.63 (s, 4H), 7.21 (d, J= 3.8 Hz, 1H), 6.96 ¨ 6.87 (m, 2H), 6.68 (dd, J= 9.0, 2.5 Hz, 1H), 6.31 (s, 2H), 4.63 (d, J= 9.2 Hz, 2H), 4.27 (d, J= 9.1 Hz, 2H), 3.83 (s, 2H), 3.72 (s, 2H), 3.67 (s, 3H), 3.25 (q, J= 7.4 Hz, 2H), 2.14 (s, 3H), 1.27 (t, J= 7.3 Hz, 3H).

Example 74 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate .0 -s-o- CN
14) N-N
N \
kN7 N\
o HN

CN
No() 0' CN
N-N
N
N-N HOO EDCI, DMAP,DCM
N \
BocHN kN N\
N \
kN' N\
HO) HN
*
Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), N-Boc-L-phenylglycine(151 mg, 0.6 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
5: 1 to 1: 2) to give the title compound as a white solid, 0.23 g, 72.5% yield. MS (m/z): [M+H] calcd for C301-134N8065, 635.23;
found,635.2.11-1 NMR (400 MHz, DMSO-d6) .3 8.97 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 7.79 (d, J= 7.8 Hz, 1H), 7.70 (s, 1H), 7.41 ¨ 7.16 (m, 6H), 6.42 ¨6.24 (m, 2H), 5.20 (d, J= 7.8 Hz, 1H), 4.63 (d, J= 9.1 Hz, 2H), 4.27 (d, J= 9.2 Hz, 2H), 3.71 (s, 2H), 3.25 (q, J= 7.3 Hz, 2H), 1.38 ¨ 1.21 (m, 12H).
Example 75 (R)-3-cyclopenty1-3-(4-(7-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile NC/-----\N-N
\
\
N \
k ----N N CI

CI
(2) a NC i---\
N-N
\

NC/----\:'" N-N
\ CI H OH
N EDCI,DMAP,DCM
N N CI
k .,---- + ci 0 HN #
N ri CI
Synthesis of (R)-3-cyclopenty1-3-(4-(7-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-(2, 6-dichloroanilino) phenylacetic acid (diclofenac, 231 mg, 0.78 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1 to 5:
1) to give the title compound as a white solid, 0.11 g, 31.4% yield. MS (m/z): [M+H] calcd for C311-127C12N70, 584.17; found, 584.1 .41 NMR (400 MHz, DMSO-d6) .3 8.99 (s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.17 (d, J= 4.1 Hz, 1H), 7.51 (d, J= 8.1 Hz, 2H), 7.41 ¨7.29 (m, 2H), 7.21 (dd, J= 17.2, 9.1 Hz, 2H), 7.15 ¨ 7.02 (m, 1H), 6.84 (t, J= 7.4 Hz, 1H), 6.25 (d, J= 8.1 Hz, 1H), 5.01 (s, 2H), 4.56 (td, J= 9.7, 4.2 Hz, 1H), 3.31 ¨3.17 (m, 2H), 2.45 (q, J= 8.5 Hz, 1H), 1.83 (dtd, J= 12.2, 7.5, 3.9 Hz, 1H), 1.68¨ 1.41 (m, 4H), 1.39¨ 1.21 (m, 3H).
Example 76 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoate -S
CN
14) N¨N
N
N
N

-S' O's CN

HO
0' CN
14) 0 N
kN' N¨N EDCI,DMAP,DCM

N
N
=
HO) 0 Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 177 mg, 0.6 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound as a white solid, 0.28 g, 82.5% yield. MS
(m/z): [M+H] calcd for C35H34N8055, 679.24; found,679.2.11-1 NMR (400 MHz, DMSO-d6) .3 8.98 (s, 1H), 8.83 (s, 1H), 8.49 (s, 1H), 7.87 ¨7.77 (m, 4H), 7.77¨ 7.66 (m, 2H), 7.62¨ 7.53 (m, 1H), 7.36 ¨ 7.27 (m, 2H), 7.23 (d, J= 3.8 Hz, 1H), 6.32 (q, J
= 10.8 Hz, 2H), 5.00 (s, 2H), 4.63 (d, J= 9.1 Hz, 2H), 4.28 (d, J= 9.1 Hz, 2H), 3.72 (s, 2H), 3.63 (t, J= 7.6 Hz, 1H), 3.28 (q, J= 7.3 Hz, 2H), 2.04¨ 1.97 (m, 1H), 1.76 (dt, J= 13.6, 7.0 Hz, 1H), 1.32¨ 1.28 (m, 3H), 0.82 (t, J
= 7.3 Hz, 3H).
Example 77 (3R)-3-cyclopenty1-3-(4-(7-(2-(4((2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d]

pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile r-NN-N
NC
N

NC N-N
NC N-N
0 0 EDCI, DMAP,DCM
OH
ICC>

Synthesis of (3R)-3-cyclopenty1-3-(4-(7-(2-(4((2-oxocyclopentyl) methyl) phenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pynolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl]
propanoic acid (loxoprofen, 192 mg, 0.78 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9mm01) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 2: 1) to give the title compound as a light yellow solid, 0.26 g, 81.1% yield. MS
(m/z): [M+H] calcd for C32H341\1602, 535.27; found,535.4.1H NMR (400 MHz, DMSO-d6) .3 8.97 (s, 1H), 8.87 (d, J= 1.6 Hz, 1H), 8.40 (s, 1H), 8.11 (d, J= 4.2 Hz, 1H), 7.34 (d, J= 7.8 Hz, 2H), 7.30 (d, J= 4.2 Hz, 1H), 7.11 (d, J=
7.8 Hz, 2H), 6.00 (q, J= 6.8 Hz, 1H), 4.55 (td, J= 9.6, 4.2 Hz, 1H), 3.31 ¨3.15 (m, 2H), 2.90 (dd, J= 13.2, 3.4 Hz, 1H), 2.38 (tdd, J = 20.0, 14.0, 5.9 Hz, 3H), 2.20 (ddd, J= 18.1, 8.2, 2.8 Hz, 1H), 2.05 (dd, J= 10.1, 8.6 Hz, 1H), 1.92¨ 1.75 (m, 3H), 1.68 ¨
1.50 (m, 7H), 1.48¨ 1.22 (m, 5H) Example 78 (R)-N-(4-(2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-ox oethyl) phenyl) acetamide NCNN
N
N"

NH
NC NI-N

EDCI, DMAP,DCM
+ AN 0 N
N

NH
Synthesis of (R)-N-(4-(2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxoethyl) phenyl) acetamide (R)-3-(4-(7h-pynolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 151 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 2: 3) to give the title compound as a light yellow solid, 0.18 g, 62.3% yield. MS (m/z): [M+H] calcd for C27H27N702, 482.22;
found,482.3.11-1 NMR (400 MHz, DMSO-d6) .3 9.90 (s, 1H), 8.97 (s, 1H), 8.90 (s, 1H), 8.43 (s, 1H), 8.12 (d, J= 4.2 Hz, 1H), 7.54 (d, J= 8.1 Hz, 2H), 7.32 (dd, J= 16.1, 6.1 Hz, 3H), 4.87 (s, 2H), 4.55 (td, J= 9.6, 4.1 Hz, 1H), 3.30¨ 3.17 (m, 2H), 2.43 (p, J=
8.5 Hz, 1H), 2.04 (s, 3H), 1.83 (dhept, J= 12.4, 4.1, 3.7 Hz, 1H), 1.67 ¨ 1.41 (m, 4H), 1.39¨ 1.16 (m, 3H).
Example 79 (R)-3-(4-(7-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile /----NN-N
NC
\
N
k-----ki N"

---/
CI

0 OH r----NC N-N
\ 1 Nr\N-N
N \ + \ EDCI,DMAP,DCM
N
k ------ 0 N ril CI /

CI
Synthesis of (R)-3-(4-(7-(2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 279 mg, 0.78 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 2: 1) to give the title compound as a light yellow solid, 0.3 g, 77.5% yield. MS (m/z): [M+H] calcd for C36H32C1N703, 646.23;
found,646.1.1H NMR (400 MHz, DMSO-d6) .3 9.03 (s, 1H), 8.93 (s, 1H), 8.47 (s, 1H), 8.16 (d, J= 4.2 Hz, 1H), 7.76 ¨ 7.63 (m, 4H), 7.38 (d, J= 4.2 Hz, 1H), 7.18 (d, J= 2.5 Hz, 1H), 7.00 (d, J= 9.0 Hz, 1H), 6.73 (dd, J = 9.1, 2.6 Hz, 1H), 5.05 (s, 2H), 4.58 (td, J
= 9.6, 4.3 Hz, 1H), 3.71 (s, 3H), 3.31 ¨3.19 (m, 2H), 2.46 (q, J= 8.2 Hz, 1H), 2.28 (s, 3H), 1.90¨ 1.80 (m, 1H), 1.68 ¨ 1.31 (m, 7H).
Example 80 Tert-butyl ((S)-2-(4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate NCr---\N-N
N \

N

\- N
NC
Nr\N-N 0 + NH EDCI,DMAP,DCM N \

N

Synthesis of tert-butyl ((S)-2-(4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1)-2-oxo-1-phenylethyl) carbamate (R)-3-(4-(7h-pynolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), N-Boc-L-phenylglycine (196 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 2: 1) to give the title compound as a yellow solid, 0.26 g, 55.6% yield. MS (m/z): [M+H] calcd for C301-133N703, 540.26; found,540.3.11-1 NMR (400 MHz, DMSO-d6) 8.97 (s, 1H), 8.87 (s, 1H), 8.41 (s, 1H), 8.14 (d, J= 4.2 Hz, 1H), 7.95 (d, J=
7.6 Hz, 1H), 7.52 (d, J= 7.3 Hz, 2H), 7.42 (d, J= 7.7 Hz, 1H), 7.31 (td, J= 11.8, 10.6, 5.4 Hz, 4H), 4.54 (td, J=
9.6, 4.3 Hz, 1H), 3.29 ¨ 3.12 (m, 2H), 2.43 (h, J= 8.5 Hz, 1H), 1.82 (dtd, J= 11.9, 7.4, 4.2 Hz, 1H), 1.65¨ 1.50 (m, 3H), 1.46¨ 1.23 (m, 13H).
Example 81 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-((3-chloro-2-methylphenyl) amino) benzoate N-N
N \
k N
N

OSCN
NH
CI
_0 S' 0-4,CN
s-0-4,CN
HO 0 N \
N-N N EDCI,DMAF N 1, DCM CI?
=CI \ N 0 kr,r N ill NH
HO
a Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-((3-chloro-2-methylphenyl) amino) benzoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 137 mg, 0.53 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a yellow solid, 0.26 g, 80.7% yield. MS (m/z): [M+H] calcd for C31H29C1N804S, 645.17; found,645.1.11-1 NMR (400 MHz, DMSO-d6) 9.12 (s, 1H), 8.98 (s, 1H), 8.84 (s, 1H), 8.52 (s, 1H), 7.93 (d, J= 3.8 Hz, 1H), 7.79 (dd, J= 8.4, 1.7 Hz, 1H), 7.37 (td, J= 7.6, 7.1, 1.7 Hz, 1H), 7.33 ¨7.21 (m, 4H), 6.78¨ 6.70 (m, 2H), 6.55 (s, 2H), 4.62 (d, J= 9.1 Hz, 2H), 4.26 (d, J= 9.1 Hz, 2H), 3.71 (s, 2H), 3.24 (q, J= 7.3 Hz, 2H), 2.24 (s, 3H), 1.26 (t, J= 7.3 Hz, 3H).
Example 82 (R)-3-cyclopenty1-3-(4-(7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile NCNN
\
\
N -"-- = \
kN----N

HN

..
NC N-N
i----\
Y'.----r\I )LL'N':-.N
+
1.1 H
N EDCI,DMAP,DCM
_______________________________________ .-0 =
H
*
Synthesis of (R)-3-cyclopenty1-3-(4-(7-(2-((2, 3-dimethylphenyl) amino) benzoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pynolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 184 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 188 mg, 0.78 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9mm01) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 4: 1 to 3:
1) to give the title compound as a yellow solid, 0.08 g, 25.2% yield. MS (m/z): [M+H] calcd for C32H3IN70, 530.26; found,530.3.11-1 NMR (400 MHz, DMSO-d6) .3 8.88 (s, 1H), 8.73 (s, 1H), 8.44 (d, J = 13.9 Hz, 2H), 7.87 (d, J = 4.0 Hz, 1H), 7.42 (ddd, J =
7.7, 4.5, 2.8 Hz, 2H), 7.29 (d, J= 4.1 Hz, 1H), 7.08 ¨7.01 (m, 2H), 6.94 (dd, J= 6.2, 2.6 Hz, 1H), 6.87 ¨ 6.75 (m, 2H), 4.56 (td, J= 9.7, 4.2 Hz, 1H), 3.29 ¨ 3.15 (m, 2H), 2.45 (q, J= 8.4 Hz, 1H), 2.22 (s, 3H), 1.98 (s, 3H), 1.83 (dtd, J= 12.3, 7.4, 3.8 Hz, 1H), 1.55 (tdt, J= 32.5, 29.7, 18.3, 6.6 Hz, 4H), 1.39¨ 1.22 (m, 3H).
Example 83 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-((2, 3-dimethylphenyl) amino) benzoate .0 -S' 0' s CN
Niq) N-N
\
N
N \
k - N

NH
..,o -S' o' = CN
Niq j CN
Niq) HO 0 N'"- \
N-N H EDCI, DMAP,DCM ., \ + N "\__.0 N N dash N --- \
ii=-=N N it NH
HO) Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-((2, 3-dimethylphenyl) amino) benzoate 2-(1-(ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 22-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 127 mg, 0.53 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a yellow solid, 0.27 g, 86.5% yield. MS (m/z): [M+H] calcd for C32H32N8045, 625.23; found,625.2.11-1 NMR (400 MHz, DMSO-d6) .3 9.06 (s, 1H), 8.98 (s, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 7.94 (d, J= 3.8 Hz, 1H), 7.76 (dd, J= 8.1, 1.7 Hz, 1H), 7.32 (ddd, J= 8.6, 7.0, 1.7 Hz, 1H), 7.27 (d, J= 3.8 Hz, 1H), 7.18 ¨7.05 (m, 3H), 6.70¨ 6.59 (m, 2H), 6.55 (s, 2H), 4.61 (d, J= 9.1 Hz, 2H), 4.25 (d, J= 9.1 Hz, 2H), 3.70 (s, 2H), 3.24 (q, J=
7.3 Hz, 2H), 2.30 (s, 3H), 2.09 (s, 3H), 1.25 (t, J= 7.3 Hz, 3H).
Example 84 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(4-acetamidophenyl) acetate .0 0' CN
NL.q) HN
N¨N
N \
N\
o .0 .5' 0' s CN

0' CN N¨N
Niq) N¨N HO EDCI, DMAP,DCM

0 N \
N\
N -"N= \
kiNr N, HO) 0 Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(4-acetamidophenyl) acetate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 116 mg, 0.6 mmol), and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound as a white solid, 0.22 g, 76.3% yield. MS
(m/z): [M+H] calcd for C27F1281\18055, 577.19; found,577.2.11-1 NMR (400 MHz, DMSO-d6) .3 9.89 (s, 1H), 8.98 (s, 1H), 8.84 (s, 1H), 8.52 (s, 1H), 7.78 (d, J= 3.8 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.19 (dd, J= 31.5, 5.9 Hz, 3H), 6.29 (s, 2H), 4.63 (d, J
= 9.1 Hz, 2H), 4.27 (d, J= 9.1 Hz, 2H), 3.69 (d, J= 20.8 Hz, 4H), 3.26 (q, J=
7.3 Hz, 2H), 2.04 (s, 3H), 1.27 (t, J
= 7.4 Hz, 3H).
Example 85 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indo1-1-y1) acetate .0 .S' 0' s CN
No\) N-N
\
N
N \
k - N
No ) H
N
/

.0 ,S' .S' .0 0' µNiL-__, ICN
--k--0' s CN
N.4 j N¨N
\
N

N¨N H OH EDCI, DMAP,DCM
\ +
N N
HO) N
/

Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b]
indo1-1-y1) acetate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 31 mg, 0.25 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole-l-acetic acid (etodolac, 172 mg, 0.6 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5: 1 to 1: 2) to give the title compound as a white solid, 0.17 g, 50.7% yield. MS (m/z): [M+H] calcd for C34F138N805S, 671.27; found,671.2.11-1 NMR (400 MHz, DMSO-d6) .3 10.42 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 7.61 (d, J= 3.8 Hz, 1H), 7.20 ¨ 7.10 (m, 2H), 6.93 ¨6.81 (m, 2H), 6.27 ¨ 6.12 (m, 2H), 4.63 (d, J= 9.1 Hz, 2H), 4.27 (d, J= 9.1 Hz, 2H), 3.88 ¨3.76 (m, 2H), 3.72 (s, 2H), 3.25 (q, J= 7.3 Hz, 2H), 3.06 (d, J= 13.6 Hz, 1H), 2.86 (d, J= 13.6 Hz, 1H), 2.81 ¨2.75 (m, 2H), 2.61 - 2.48 (m, 2H), 2.01 - 1.80 (m, 2H), 1.30¨ 1.21 (m, 6H), 0.58 (t, J= 7.3 Hz, 3H).
Example 86 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate NCNN

NC
'N-N
y NC. -N NNC r OH
SEMCI DIPEA DCM NC TFA, DCM r t 16h EDCI DMA, DCM
N \
-OH
First step: step: Synthesis of (R)-3-cyclopenty1-3-(4-(7((2-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 1000 mg, 3.26 mmol) and N, N-diisopropylethyl amine (0.7 mL, 4.9 mmoL) were added in dichloromethane (8 mL) under nitrogen. After stirring at room temperature for half an hour, (2-(chloromethoxy) ethyl) trimethylsilane (0.65 g, 3.92 mmol) was added in an ice-water bath, and stirring was continued at room temperature for 3 hours. The reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound 1.4 g, 98.5% yield. MS
(m/z): [M+H] calcd for C23H32N60Si, 437.24;found, 437.3.
Step 2: Synthesis of (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile Trifluoroacetic acid (9 mL, 13.8 mg, 121 mmol) was slowly added dropwise to a solution of (R)-3-cyclopenty1-3-(4-(7((2-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (1.4 g, 3.2 mmol) in dichloromethane (90 mL) under nitrogen in an ice-water bath. After half an hour, the ice-water bath was removed. The temperature was raised to room temperature and stirring was continued for an additional 2 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0 C to adjust the pH to 8. Then the mixture was poured into a separating funnel for separation. The organic layer was washed with a saturated salt water solution and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 100:

1 to 30: 1) to give the title product 0.36 g, 33.4% yield. MS (m/z): [M+H]
calcd for C18H20N60, 337.17;found, 337.3. 1H NMR (400 MHz, DMSO-d6) .3 8.95 ¨ 8.80 (m, 2H), 8.49 (s, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.15 (d, J =
3.7 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 5.72 (d, J = 7.3 Hz, 2H), 4.64 (td, J =
9.6, 4.2 Hz, 1H), 3.42 ¨ 3.26 (m, 2H), 2.53 (q, J = 8.5 Hz, 1H), 1.92 (dtd, J = 11.8, 7.5, 4.2 Hz, 1H), 1.76¨ 1.50 (m, 4H), 1.50¨ 1.23 (m, 3H).
Step 3: synthesis of (4-(14(R)-2-cyano-l-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (120 mg, 0.36 mmol), 4-dimethylamino pyridine (DMAP, 44 mg, 0.36 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 110 mg, 0.54 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 103 mg, 0.54 mmol) were dissolved in a mixed solvent of dichloromethane (2.5 mL) and dimethylformamide (0.25 mL) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.106 g, 56.1% yield. MS (m/z): [M+H] calcd for C311-136N602, 525.29; found, 525.3.1H
NMR (400 MHz, Chloroform-d) .3 8.85 (s, 1H), 8.31 (d, J= 10.9 Hz, 2H), 7.41 (d, J= 3.8 Hz, 1H), 7.10 (d, J= 8.1 Hz, 2H), 7.00 (d, J= 7.9 Hz, 2H), 6.72 (d, J= 3.8 Hz, 1H), 6.30¨ 6.18 (m, 2H), 4.28 (ddd, J= 10.1, 8.6, 4.0 Hz, 1H), 3.71 (q, J= 7.1 Hz, 1H), 3.14 (dd, J= 17.0, 8.6 Hz, 1H), 2.97 (dd, J= 17.0, 4.0 Hz, 1H), 2.61 (ddd, J=
16.8, 8.2, 4.6 Hz, 1H), 2.40 (d, J=
7.1 Hz, 2H), 2.00¨ 1.93 (m, 1H), 1.85 ¨ 1.53 (m, 6H), 1.47 (d, J= 7.2 Hz, 3H), 1.37¨ 1.23 (m, 2H), 0.86 (d, J=
6.6 Hz, 6H).
Example 87 (4-(14(R)-2-cyano-l-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate C
i¨\N-N
NC
N"--------/

NC -N
NC N-N HO EDCI, DMAP, DCM

OH I
r\C

N

Synthesis of (4-(14(R)-2-cyano-l-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (140 mg, 0.42 mmol), 4-dimethylamino pyridine (DMAP, 51 mg, 0.42 mmol), (S)--(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 144 mg, 0.63 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 120 mg, 0.63 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.146 g, 63.4% yield. MS (m/z):
[M+H] calcd for C32H32N603, 549.25; found, 549.3.1H NMR (400 MHz, Chloroform-d) .3 8.83 (s, 1H), 8.29 (d, J= 7.0 Hz, 2H), 7.60 (t, J= 8.6 Hz, 2H), 7.54 (d, J= 1.8 Hz, 1H), 7.39 (d, J= 3.8 Hz, 1H), 7.29 (dd, J= 6.6, 1.9 Hz, 1H), 7.14 ¨ 7.03 (m, 2H), 6.68 (d, J= 3.8 Hz, 1H), 6.24 (d, J= 2.4 Hz, 2H), 4.27 (ddd, J= 10.1, 8.6, 4.0 Hz, 1H), 3.89 (s, 3H), 3.14 (dd, J=
17.0, 8.6 Hz, 1H), 2.96 (dd, J= 17.0, 4.0 Hz, 1H), 2.66 ¨ 2.53 (m, 1H), 2.05 ¨
1.92 (m, 1H), 1.79 ¨ 1.50 (m, 9H), 1.29 (td, J= 12.8, 6.5 Hz, 2H).
Example 88 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate H

0, 0, 0 µ1J..
- I OH
SEMCI DIPEA DCM \--0 TFA DCM
tj --OH EDO! MAP DOM

C
First step: synthesis of N-methyl-1-((trans)-4-(methyl (7-02-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide N-Methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 1687 mg, 5 mmol) and N, N-diisopropylethyl amine (780 mg, 6 mmol) were added in dichloromethane (50 mL) under nitrogen. After stirring at room temperature for half an hour, (2-(chloromethoxy) ethyl) trimethylsilane (1 g, 6 mmol) was added in an ice-water bath. Stirring was continued at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to give the title compound as an oily solid, 2 g, 85.6%
yield. MS (m/z): [M+H] calcd for C211-137N503SSi, 468.24;found, 468.2.
Step 2: synthesis of 1-((trans)-4-((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide Trifluoroacetic acid (6 mL, 9.2 g, 80.8 mmol) was slowly added dropwise to a solution of N-methy1-1-((trans)-4-(methyl (7((2-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (2 g, 4.29 mmol) in dichloromethane (60 mL) under nitrogen in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 24 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0 C to adjust the pH to 8. Then the mixture was poured into a separating funnel for separation. The organic layer was washed with a saturated salt water solution and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 1 to 0: 1) to give the title product, 0.9 g, 98.5% yield. MS (m/z): [M+H] calcd for C16H25N5035, 368.17;found, 368.2.
Step 3: synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (150 mg, 0.41 mmol), 4-dimethylaminopyridine (DMAP, 50 mg, 0.41 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 126 mg, 0.61 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 117 mg, 0.61mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1 to 1: 2) to give the title compound as a white solid, 0.086 g, 37.7% yield. MS (m/z): [M+H] calcd for C29H4IN5045, 556.29; found, 556.3 .1H
NMR (400 MHz, Chloroform-d) .3 8.32 (s, 1H), 7.11 (d, J= 7.7 Hz, 2H), 7.08 ¨ 6.94 (m, 3H), 6.48 (d, J= 3.8 Hz, 1H), 6.22 ¨ 6.04 (m, 2H), 4.75 (s, 1H), 4.31 (q, J= 5.3 Hz, 1H), 3.68 (q, J= 7.2 Hz, 1H), 3.20 (s, 3H), 2.96 (d, J= 6.2 Hz, 2H), 2.82 (d, J= 5.1 Hz, 3H), 2.41 (d, J= 7.1 Hz, 2H), 2.24 ¨ 2.13 (m, 2H), 2.06¨ 1.95 (m, 1H), 1.84 (ddd, J= 22.7, 13.2, 5.3 Hz, 3H), 1.76¨ 1.62 (m, 2H), 1.44 (d, J= 7.3 Hz, 3H), 1.36 (dd, J= 12.4, 9.1 Hz, 2H), 0.87 (d, J= 6.6 Hz, 6H).
Example 89 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate N

-S
H
EDCI, DMAP,DCM
HO
N
0 o Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-(6-methoxynaphthalen-2-y1) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (150 mg, 0.41 mmol), 4-dimethylamino pyridine (DMAP, 50 mg, 0.41 mmol), (S)-(+)-2-(6-methoxy-2-naphthyl) propanoic acid (naproxen, 141 mg, 0.61mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 117 mg, 0.61 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1 to 1: 2) to give the title compound as a white solid, 0.056 g, 23.5% yield. MS (m/z): [M+H] calcd for C301-137N5055, 580.25; found, 580.3 .1H
NMR (400 MHz, Chloroform-d) .3 8.31 (s, 1H), 7.69 ¨ 7.44 (m, 3H), 7.40 ¨ 7.22 (m, 1H), 7.17 ¨ 6.99 (m, 3H), 6.43 (d, J= 3.8 Hz, 1H), 6.14 (q, J

= 10.6 Hz, 2H), 4.72 (s, 1H), 4.24 (q, J= 5.4 Hz, 1H), 3.97¨ 3.78 (m, 4H), 3.17 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.82 (d, J= 5.3 Hz, 3H), 2.16 (d, J= 13.1 Hz, 2H), 1.99 (s, 1H), 1.85 (d, J=
11.1 Hz, 2H), 1.74¨ 1.60 (m, 2H), 1.53 (d, J= 7.2 Hz, 3H), 1.36 (td, J= 13.7, 5.9 Hz, 2H).
Example 90 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate c\I\

N
0 EDCI, DMAP,DCM
N OH N

N

Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-(3 -benzoylphenyl) propanoic acid (ketoprofen, 198 mg, 0.78 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 2) to give the title compound as a white solid, 0.16 g, 44.2% yield. MS (m/z): [M+H] calcd for C32H371\15055, 604.25; found,604.4.1H
NMR (400 MHz, DMSO-d6) 8.12 (s, 1H), 7.71 ¨7.65 (m, 3H), 7.61 ¨7.51 (m, 5H), 7.46 (t, J= 8.0 Hz, 1H), 7.23 (d, J= 3.8 Hz, 1H), 6.88 (q, J
= 4.9 Hz, 1H), 6.60 (d, J= 3.7 Hz, 1H), 6.14 (s, 2H), 4.63 (s, 1H), 3.95 (q, J= 7.1 Hz, 1H), 3.13 (s, 3H), 2.95 (d, J
= 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.09 ¨ 2.01 (m, 2H), 1.81 (s, 1H), 1.72¨ 1.62 (m, 4H), 1.39 (d, J= 7.1 Hz, 3H), 1.35¨ 1.26 (m, 2H).
Example 91 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate H
HN
N
0 =

,S
-S

0 NH EDCI, DMAP,DCM
N +
OH _________________________________________ 40 '101 N
0 Hi, \<0 Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), N-Boc-L-phenylglycine (196 mg, 0.78 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate =
2: 1 to 1: 2) to give the title compound as a white solid, 0.14 g, 38.8% yield. MS (m/z): [M+H] calcd for C29H40N6065, 601.27; found,601.4.
1H NMR (400 MHz, DMSO-d6) .3 8.21 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.39 ¨
7.25 (m, 6H), 6.94 (q, J = 5.0 Hz, 1H), 6.67 (d, J= 3.8 Hz, 1H), 6.27 ¨ 6.16 (m, 2H), 5.22 (d, J= 7.9 Hz, 1H), 4.71 (s, 1H), 3.21 (s, 3H), 3.01 (d, J=
6.2 Hz, 2H), 2.64 (d, J= 5.0 Hz, 3H), 2.10 (d, J= 12.7 Hz, 2H), 1.95¨ 1.85 (m, 1H), 1.73 (d, J= 7.5 Hz, 4H), 1.41 (s, 11H).
Example 92 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate 9\
.S
'N
CI

CI
(:),µ H0O,N
CI
HO EDCI, DMAP,DCM.. 11'N N
HN CI

N OH

CI
Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 2-(2, 6-dichloroanilino) phenylacetic acid (diclofenac, 444 mg, 1.5 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1: 1) to give the title compound as a white solid, 0.14 g, 36.2% yield. MS (m/z): [M+H] calcd for C30H34C12N6045, 645.17; found,645.3.1H
NMR (400 MHz, DMSO-d6) .3 8.17 (s, 1H), 7.52 (d, J= 8.1 Hz, 2H), 7.30 (d, J= 3.8 Hz, 1H), 7.24 ¨ 7.12 (m, 2H), 7.05 (td, J= 7.7, 1.6 Hz, 1H), 6.95 (s, 1H), 6.87 (q, J= 4.9 Hz, 1H), 6.82 (td, J= 7.4, 1.2 Hz, 1H), 6.64 (d, J= 3.8 Hz, 1H), 6.23 (dd, J=
8.0, 1.2 Hz, 1H), 6.19 (s, 2H), 4.66 (s, 1H), 3.82 (s, 2H), 3.16 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.05 (d, J= 12.1 Hz, 2H), 1.82 (s, 1H), 1.75¨ 1.65 (m, 4H), 1.30 (q, J=
7.9, 7.2 Hz, 2H).
Example 93 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate 'N
N
HN

,S
CZ
1\1"µSµ10 HrN

OH
).,N EDCI, DMAP,DCM
N N
\--OH
HN
Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylaminopyridine (DMAP, 7 mg, 0.06 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 151 mg, 0.78 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9mm01) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 0: 1) to give the title compound as a white solid, 0.016 g, 49.2% yield. MS (m/z): [M+H] calcd for C26H341\16055, 543.23; found,543.3.11-1 NMR (400 MHz, DMSO-d6) 9.89 (s, 1H), 8.19 (s, 1H), 7.54 ¨ 7.39 (m, 2H), 7.29 (d, J= 3.8 Hz, 1H), 7.19¨ 7.09 (m, 2H), 6.87 (q, J= 4.9 Hz, 1H), 6.65 (d, J= 3.7 Hz, 1H), 6.14 (s, 2H), 4.67 (s, 1H), 3.61 (s, 2H), 3.17 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.03 (s, 5H), 1.84 (s, 1H), 1.70 (q, J= 6.7 Hz, 4H), 1.37¨
1.27 (m, 2H).
Example 94 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-b] indol -1-y1) acetate 9\
I\J-S\M-3 H -) H

9, .S
H , 0 H OH
EDCI, DMAP,DCM
N.=
0 0 ) Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 241, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-b]
indo1-1-y1) acetate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (220 mg, 0.6 mmol), 4-dimethylamino pyridine (DMAP, 7 mg, 0.06 mmol), 21, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole-l-acetic acid (etodolac, 224 mg, 0.78 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 173 mg, 0.9 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 0: 1) to give the title compound as a white solid, 0.14 g, 36.6% yield. MS (m/z): [M+H] calcd for C33H44N605S, 637.31; found, 637.3.1H
NMR (400 MHz, DMSO-d6) 10.42 (s, 1H), 8.18 (s, 1H), 7.20 (dd, J= 7.6, 1.4 Hz, 1H), 7.13 (d, J= 3.8 Hz, 1H), 6.94 ¨ 6.84 (m, 3H), 6.56 (d, J
= 3.8 Hz, 1H), 6.13 ¨ 6.02 (m, 2H), 4.66 (s, 1H), 3.92 ¨ 3.77 (m, 2H), 3.17 (s, 3H), 3.06 ¨ 2.92 (m, 3H), 2.88 ¨
2.76 (m, 3H), 2.69 ¨ 2.56 (m, 5H), 2.10 ¨ 2.00 (m, 3H), 1.93 ¨ 1.81 (m, 2H), 1.76¨ 1.64 (m, 4H), 1.39¨ 1.27 (m, 2H), 1.26¨ 1.18 (m, 3H), 0.59 (t, J= 7.3 Hz, 3H).
Example 95 2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile .0 0' CN
14) N-N

-S
0' *CN
-S' 0' = CN
14) 0 EDCI,DMAP,DCM
OH rt, 3h NILL

Synthesis of 2-(1-(ethylsulfony1)-3-(4-(7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile 1-(Ethylsulfony1)-344-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1]-3-azetidine acetonitile (baricitinib, 1113 mg, 3mm01), 4-dimethylamino pyridine (DMAP, 36.6mg, 0.3mm01), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 742 mg, 3.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 864 mg, 4.5 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1 to 1:
2) to give the title compound as a white solid, 0.12 g, 71.5% yield. MS (m/z): [M+H] calcd for C29H33N7035, 560.69; found, 560.3.1H NMR (400 MHz, DMSO-d6) .3 8.99 (d, J= 4.2 Hz, 2H), 8.50 (s, 1H), 8.14 (d, J= 4.2 Hz, 1H), 7.40 (d, J= 4.2 Hz, 1H), 7.37 ¨
7.29 (m, 2H), 7.08 (d, J= 7.9 Hz, 2H), 5.99 (q, J= 6.9 Hz, 1H), 4.59 (d, J=
9.1 Hz, 2H), 4.24 (d, J= 9.1 Hz, 2H), 3.68 (s, 2H), 3.23 (q, J= 7.3 Hz, 2H), 2.35 (d, J= 7.2 Hz, 2H), 1.76 (hept, J=
6.7 Hz, 1H), 1.58 (d, J= 6.9 Hz, 3H), 1.24 (t, J= 7.3 Hz, 3H), 0.80 (d, J= 6.6 Hz, 6H).
Example 96 1-((Trans)-4-((7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide 9\
H
kN--1\1 R\
N
CZ, H

EDCI,DMAP,DCM
N OH
rt, 16 h Synthesis of 1-((trans)-4-((7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide N-methy1-1-((trans)-4-(methyl (7H-pyrrolo [2, 3-d] pyrimidin -4-y1) amino) cyclohexyl) methanesulfonamide (oclacitinib, 150 mg, 0.44 mmol), 4-dimethylamino pyridine (DMAP, 6 mg, 0.044 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 96 mg, 0.468 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 128 mg, 0.666 mmol) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 4: 1 to 2: 1) to give the title compound as a white solid, 0.07 g, 30% yield. MS (m/z):
[M+H] calcd for C28H39N5035, 526.28;
found, 526.1.1H NMR (400 MHz, DMSO-d6) .3 8.36 (s, 1H), 7.66 (d, J= 4.2 Hz, 1H), 7.33 ¨7.26 (m, 2H), 7.07 (d, J= 8.0 Hz, 2H), 6.95 ¨6.81 (m, 2H), 6.10 (q, J= 6.9 Hz, 1H), 4.66 (s, 1H), 3.15 (s, 3H), 2.94 (d, J= 6.2 Hz, 2H), 2.58 (d, J= 5.0 Hz, 3H), 2.36 (d, J= 7.1 Hz, 2H), 2.10 ¨ 1.96 (m, 2H), 1.91 ¨
1.60 (m, 6H), 1.52 (d, J= 7.0 Hz, 3H), 1.35¨ 1.22 (m, 2H), 0.82 (d, J= 6.7 Hz, 6H).
Example 97 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide rCN
N- N

N

N' 'a rCI\I
OH 0 n N N DIAD,PPh3 0 0 r)THF
N

Synthesis of 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (piroxicam, 66 mg, 0.2 mmol) and tiphenylphosphine (PPh3, 79 mg, 0.3 mmol) were added to tetrahydrofuran (0.4 mL) and stirred under nitrogen. After cooling to -10 C, diisopropyl azodicarboxylate (DIAD, 53 mg, 0.26 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature naturally. 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitile (68 mg, 0.2 mmol) was added and stirring was continued. The reaction was monitored by TLC. After complete exhaust of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9:
1) to give the title compound as a yellow solid, 0.005 g, 3.8% yield. MS (m/z): [M+H] calcd for C32H33N9055, 656.23, found 656.2.1H NMR (400 MHz, Chloroform-d) .3 15.22 (d, J = 17.7 Hz, 1H), 8.52 (t, J = 8.4 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.23 (d, J =
3.1 Hz, 1H), 8.07 ¨ 7.91 (m, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.71 ¨ 7.55 (m, 3H), 6.70 ¨ 6.58 (m, 2H), 6.51 (dd, J =
9.8, 3.8 Hz, 1H), 4.95 (s, 1H), 4.06 (dd, J = 13.0, 4.4 Hz, 1H), 3.85 ¨ 3.67 (m, 1H), 3.66 ¨ 3.55 (m, 1H), 3.54 ¨
3.36 (m, 4H), 3.27 (d, J = 18.4 Hz, 3H), 3.03 (s, 3H), 2.53 ¨ 2.39 (m, 1H), 1.95 ¨ 1.85 (m, 1H), 1.73 ¨ 1.61 (m, 1H), 1.01 (t, J = 7.7 Hz, 3H).
Example 98 (R)-3-cyclopenty1-3-(4-(7-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile NCi-\N-N
N

C i----NC N-N
NC N-N
Y+ 0 EDCI,DMAP,DCM
N -,- 'N--2----N
IC-2:1 Synthesis of (R)-3-cyclopenty1-3-(4-(7-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (R)-3-(4-(7h-pyrrolo [2, 3-d] pyridin -4-y1)-1h-pyrazol-1-y1)-3-cyclopentylpropane (Ruxolitinib, 50 mg, 0.163 mmol), 4-dimethylamino pyridine (DMAP, 2 mg, 0.016 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 35.5 mg, 0.172 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 47 mg, 0.245 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (petroleum ether/ethyl acetate = 4: 1 to 3: 1) to give the title compound as a white solid, 0.05 g, 61% yield. MS (m/z): [M+H] calcd for C30H34N604, 495.64; found, 495.2.1H NMR (400 MHz, DMSO-d6) .3 8.97 (s, 1H), 8.88 (d, J= 1.6 Hz, 1H), 8.39 (d, J= 11.3 Hz, 1H), 8.12 (d, J= 4.2 Hz, 1H), 7.40 - 7.28 (m, 3H), 7.09 (dd, J= 7.9, 5.8 Hz, 2H), 6.00 (q, J= 6.9 Hz, 1H), 4.54 (td, J=
9.6, 4.6 Hz, 1H), 3.28 -3.15 (m, 2H), 2.47 - 2.31 (m, 3H), 1.88- 1.71 (m, 2H), 1.65 - 1.40 (m, 5H), 1.40- 1.16 (m, 5H), 0.99 - 0.76 (m, 6H).
Example 99 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate a NC/¨\N-N
\
N
N \
kN' N
o) HO NC N-N

F-C
NC N-N 0 EDCI, DMAP, DCM N \

Q-Kr N
ICn \--OH 0 Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-benzoylphenyl) propanoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 191 mg, 1.5 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution.
The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.143 g, 50% yield. MS
(m/z): [M+H] calcd for C34H32N603, 573.25; found, 573.3.1H NMR (400 MHz, DMSO-d6) .3 8.83 (d, J= 0.7 Hz, 1H), 8.72 (s, 1H), 8.38 (s, 1H), 7.69 (d, J= 3.8 Hz, 1H), 7.68 ¨7.62 (m, 3H), 7.58 (d, J= 1.8 Hz, 1H), 7.57 ¨ 7.49 (m, 4H), 7.44 (t, J= 7.6 Hz, 1H), 7.08 (d, J= 3.8 Hz, 1H), 6.33 ¨ 6.22 (m, 2H), 4.55 (td, J = 9.7, 4.2 Hz, 1H), 3.99 (q, J= 7.0 Hz, 1H), 3.32¨ 3.15 (m, 2H), 2.48 ¨2.35 (m, 1H), 1.87¨ 1.76 (m, 1H), 1.67¨ 1.44 (m, 3H), 1.42 ¨
1.37 (m, 3H), 1.36¨ 1.13 (m, 4H).
Example 100 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1'-bipheny11-4-y1) propanoate NC N-N
N \
kr\r N

HO NC/¨\N-N
NC N-N 0 EDCI, DMAP, DCM N \
N
OH
o) Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoate (R)-3-cyclopenty1-3-(4(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 183 mg, 0.75 mmol), and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.15 g, 53.3% yield. MS
(m/z): [M+H] calcd for C33H3IFN602, 563.25; found, 563.3.41 NMR (400 MHz, DMSO-d6) .3 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.73 (d, J= 3.7 Hz, 1H), 7.50 ¨ 7.31 (m, 6H), 7.17 ¨
7.07 (m, 3H), 6.35 ¨6.24 (m, 2H), 4.54 (td, J= 9.7, 4.2 Hz, 1H), 3.92 (q, J= 7.1 Hz, 1H), 3.33 ¨3.14 (m, 2H), 2.42 (h, J= 8.5 Hz, 1H), 1.82 (dtd, J=

12.0, 7.6, 4.5 Hz, 1H), 1.64¨ 1.48 (m, 3H), 1.48¨ 1.11 (m, 7H).
Example 101 (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate r-CN-N
NC
N \
N
o) CI HN
CI

a NC N-N

HO N
i----NC N-N 0 EDCI, DMAP, DOM N
+ CI HN N N\
NXI) IF CI al \¨OH 0 CI HN
* CI
Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetate (R)-3-cyclopenty1-3-(4(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2, 6-dichloroanilino) phenylacetic acid (diclofenac, 222 mg, 0.75 mmol), and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) was dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.12 g, 39.1% yield. MS
(m/z): [M+H] calcd for C32H29C12N702, 614.18; found,614.2.1H NMR (400 MHz, DMSO-d6) .3 8.86 ¨ 8.73 (m, 2H), 8.40 (s, 1H), 7.81 ¨7.68 (m, 2H), 7.49 (d, J= 8.1 Hz, 2H), 7.26 ¨ 6.94 (m, 4H), 6.81 (td, J= 7.4, 1.1 Hz, 1H), 6.31 (s, 2H), 6.21 (d, J= 8.1 Hz, 1H), 4.55 (td, J= 9.7, 4.2 Hz, 1H), 3.87 (d, J= 14.3 Hz, 2H), 3.24 (qd, J= 17.2, 6.9 Hz, 2H), 2.43 (h, J= 8.3 Hz, 1H), 1.82 (qt, J= 7.5, 5.4, 4.1 Hz, 1H), 1.67¨ 1.40 (m, 4H), 1.40¨ 1.13 (m, 3H).
Example 102 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-phenoxyphenyl) propanoate a i----\
NC N - N
V
1\11 c.) * 0 b (12:1 ;=
0 HO NC\N-N
\
N

NC N-N EDCI, DMAP, DCM
V + 0 N \
kre---N
\-OH 0 b Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-phenoxyphenyl) propanoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 182 mg, 0.75 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.133 g, 457.5% yield.
MS (m/z): [M+H] calcd for C33H32N603, 561.25; found, 561.4. 1H NMR (400 MHz, DMSO-d6) .3 8.83 (s, 1H), 8.74 (s, 1H), 8.40 (s, 1H), 7.67 (d, J= 3.8 Hz, 1H), 7.33 (dd, J= 8.5, 7.3 Hz, 2H), 7.24 (t, J= 7.9 Hz, 1H), 7.14 ¨
7.05 (m, 2H), 6.97 (dt, J= 7.7, 1.2 Hz, 1H), 6.93 ¨6.86 (m, 2H), 6.86 ¨ 6.75 (m, 2H), 6.32 ¨ 6.20 (m, 2H), 4.55 (td, J= 9.7, 4.2 Hz, 1H), 3.83 (q, J= 7.0 Hz, 1H), 3.28 (dd, J= 17.2, 9.6 Hz, 1H), 3.19 (dd, J= 17.2, 4.2 Hz, 1H), 2.42 (h, J= 8.6 Hz, 1H), 1.82 (dtd, J= 11.9, 7.5, 4.4 Hz, 1H), 1.66¨ 1.43 (m, 4H), 1.43¨ 1.12 (m, 6H).
Example 103 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate i---N
NC N-N
\
N
N \
kr\l' N
) NC "
HO N
N
NC " 0 EDCI, DMAP, DCM 0) r(P 0 Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 185 mg, 0.75 mmol), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5mL) and dimethylformamide (0.3mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.125 g, 44.3% yield.
MS (m/z): [M+H] calcd for C33H36N603, 565.28; found, 565.3. 11-1 NMR (400 MHz, DMSO-d6) .3 8.82 (s, 1H), 8.74 (d, J= 1.7 Hz, 1H), 8.39 (s, 1H), 7.68 (d, J= 3.8 Hz, 1H), 7.11 ¨6.96 (m, 5H), 6.28 ¨ 6.19 (m, 2H), 4.54 (td, J= 9.6, 4.2 Hz, 1H), 3.76 (q, J= 7.0 Hz, 1H), 3.23 (qd, J= 17.1, 6.9 Hz, 2H), 2.92 ¨ 2.82 (m, 1H), 2.50 ¨ 2.14 (m, 5H), 2.08¨ 1.89 (m, 1H), 1.86¨ 1.74 (m, 3H), 1.69¨ 1.47 (m, 4H), 1.40¨ 1.12 (m, 7H).
Example 104 (R)-2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate NCNN
N \
N
N 0) CI

:-/----\
NC N-N
\
N.
a HO
N \
r----\ 0 NC N-N EDCI, DMAP, DCM ___. U----N' N
V N 0 ___________ +
/
N''''''''-------$ 0 ___.
U'N.P.--N N 0 \--OH CI 0 /
CI
Synthesis of (R)-2-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate (R)-3-cyclopenty1-3-(4(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a light yellow solid, 0.176 g, 52.1% yield. MS (m/z): [M+H] calcd for C37H34C1N704, 676.24; found,676.3. 1H
NMR (400 MHz, DMSO-d6) .3 8.84 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.71 (d, J= 3.8 Hz, 1H), 7.62 (s, 4H), 7.10 (d, J= 3.8 Hz, 1H), 6.95 -6.85 (m, 2H), 6.66 (dd, J= 9.0, 2.5 Hz, 1H), 6.29 (s, 2H), 4.55 (td, J= 9.7, 4.2 Hz, 1H), 3.82 (s, 2H), 3.65 (s, 3H), 3.32 - 3.15 (m, 2H), 2.42 (p, J= 8.5 Hz, 1H), 2.13 (s, 3H), 1.89 - 1.76 (m, 1H), 1.59 (dddd, J= 26.4, 12.6, 7.1, 4.5 Hz, 3H), 1.41 - 1.12 (m, 4H).
Example 105 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoate , i----\
NC N-N
\
N
N --- \
1,r\r N
\----0 N

CI
z=
r----\
NC N-N
N

NC N-N
EDCI, ________________________________ DMAP, DCM o V + 0 N

XN
1\ik Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (20 mg, 0.058 mmol), 4-dimethylamino pyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 26 mg, 0.09 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 17 mg, 0.09 mmol) were dissolved in a mixed solvent of dichloromethane (0.5 mL) and N, N-dimethylformamide (0.05 mL) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution.
The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.152 g, 49.6% yield. MS (m/z): [M+H]+ calcd for C36H35N703, 614.28; found,614.4 . 1H
NMR (400 MHz, DMSO-d6) .3 8.83 (s, 1H), 8.38 (s, 1H), 7.79 (t, J= 8.5 Hz, 3H), 7.74 ¨7.67 (m, 2H), 7.67¨
7.62 (m, 1H), 7.54 (td, J= 7.2, 1.5 Hz, 1H), 7.29 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 3.7 Hz, 1H), 6.35 ¨6.21 (m, 2H), 4.96 (s, 2H), 4.53 (td, J= 9.6, 4.2 Hz, 1H), 3.58 (t, J= 7.6 Hz, 1H), 3.23 (qd, J= 17.2, 6.9 Hz, 2H), 2.42 (h, J=
8.4 Hz, 1H), 2.07¨ 1.88 (m, 1H), 1.81 (dtd, J= 12.1, 7.6, 4.4 Hz, 1H), 1.76¨ 1.40 (m, 5H), 1.40¨ 1.11 (m, 4H), 0.77 (t, J= 7.3 Hz, 3H).
Example 106 (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) benzoate NCr--- \N-N
\
N
N \
kr,r N

0 *
HN

(221 N-N
NC ['NN HO NC

EDCI DMAP, DCM N`

HN
=
0 *
OH HN
Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) benzoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 181 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5mL) and N, N-dimethylformamide (0.3 mL)and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a yellow solid, 0.147 g, 52.6% yield. MS (m/z): [M+H] calcd for C33H33N702, 560.27; found, 560.3.41 NMR (400 MHz, DMSO-d6) 9.08 (s, 1H), 8.84 (d, J= 18.4 Hz, 2H), 8.42 (s, 1H), 7.91 (d, J= 3.8 Hz, 1H), 7.75 (dd, J= 8.1, 1.6 Hz, 1H), 7.32 (ddd, J= 8.8, 7.2, 1.7 Hz, 1H), 7.20 ¨ 7.00 (m, 4H), 6.69 ¨ 6.59 (m, 2H), 6.54 (s, 2H), 4.55 (td, J= 9.7, 4.2 Hz, 1H), 3.24 (qd, J= 17.2, 6.9 Hz, 2H), 2.43 (q, J= 8.4 Hz, 1H), 2.29 (s, 3H), 2.08 (s, 3H), 1.82 (dtd, J= 12.0, 7.4, 3.9 Hz, 1H), 1.65 ¨ 1.50 (m, 3H), 1.49¨ 1.12 (m, 4H).
Example 107 (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-((3-chloro-2-methylphenyl) amino) benzoate Nr\N-N
N \
r\r N

HN
'CI

NC N-N

NCF-\N-N 0 EDCI, DMAP, DCM N \
HN
kNN OH r N
1\> CI

HN
'CI
Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-((3-chloro-2-methylphenyl) amino) benzoate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (200 mg, 0.58 mmol), 4-dimethylamino pyridine (DMAP, 35 mg, 0.29 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 230 mg, 0.88 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 168 mg, 0.88 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N, N-dimethylformamide (0.2 OmL) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution.
The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a yellow solid, 0.161 g, 55.6% yield. MS (m/z): [M+H] calcd for C32H30C1N702, 580.21; found, 580.3.1H NMR (400 MHz, DMSO-d6) .3 9.13 (s, 1H), 8.83 (d, J= 18.6 Hz, 2H), 8.42 (s, 1H), 7.90 (d, J= 3.8 Hz, 1H), 7.78 (dd, J= 8.0, 1.6 Hz, 1H), 7.37 (ddd, J= 8.8, 7.1, 1.7 Hz, 1H), 7.32¨ 7.21 (m, 3H), 7.17 (d, J= 3.8 Hz, 1H), 6.78 ¨6.68 (m, 2H), 6.54 (s, 2H),4.55 (td, J= 9.6, 4.2 Hz, 1H), 3.33 ¨3.15 (m, 2H), 2.43 (q, J= 8.4 Hz, 1H), 2.24 (s, 3H), 1.82 (dtd, J= 11.9, 7.4, 4.2 Hz, 1H), 1.59 (ddd, J= 23.3, 7.9, 5.7 Hz, 2H), 1.47¨ 1.12 (m, 5H).
Example 108 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-isobutylphenyl) propanoate NC N-N
N \
N
N

CI NC /----\
N-N
\
HO N
Nr\N-N + 0 c) EDCI, DMAP, DCM
kl\r N
kN--"'---N
--_OH 0 Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-isobutylphenyl) propanoate (R)-3-cyclopenty1-3-(4(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 123.6 mg, 0.6 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.145 g, 55.3% yield. MS (m/z): [M+H] calcd for C31H36N602, 525.29, found 525.3.1H NMR (400 MHz, DMSO-d6) .3 8.83 (s, 1H), 8.74 (s, 1H), 8.39 (s, 1H), 7.68 (d, J= 3.8 Hz, 1H), 7.12 ¨ 7.02 (m, 3H), 6.95 (d, J= 7.9 Hz, 2H), 6.25 (q, J= 10.7 Hz, 2H), 4.55 (td, J= 9.7, 4.2 Hz, 1H), 3.76 (q, J= 7.0 Hz, 1H), 3.30 ¨ 3.15 (m, 2H), 2.43 (q, J= 8.5 Hz, 1H), 2.32 (d, J= 7.1 Hz, 2H), 1.89 ¨ 1.77 (m, 1H), 1.70 (hept, J= 6.8 Hz, 1H), 1.64 ¨
1.48 (m, 3H), 1.41 ¨ 1.13 (m, 7H), 0.76 (dd, J= 6.6, 1.0 Hz, 6H).
Example 109 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-b] indol -1-y1) acetate a /----\
NC N-N
\
N
N ---- \
ki,r N
) N
/

Cli .., NC\N-N
a N \
I-----\ HO N
NC N-N H EDCI, DMAP, DCM
+

/
N
/

Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-b] indol -1-y1) acetate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (171 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole-1 -acetic acid (etodolac, 216 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.153 g, 50.5% yield. MS (m/z): [M+H] calcd for C35H39N703, 606.31; found, 606.3.1H NMR (400 MHz, DMSO-d6) .3 10.42 (s, 1H), 8.83 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 7.56 (dd, J= 3.8, 1.5 Hz, 1H), 7.15 (dd, J= 7.3, 1.5 Hz, 1H), 7.01 (d, J= 3.7 Hz, 1H), 6.90 ¨
6.79 (m, 2H), 6.19 (d, J= 1.4 Hz, 2H), 4.56 (td, J= 9.7, 4.2 Hz, 1H), 3.82 (td, J= 11.1, 5.4 Hz, 2H), 3.31 ¨3.15 (m, 2H), 3.05 (d, J= 13.6 Hz, 1H), 2.88 ¨2.69 (m, 3H), 2.60 (ddd, J= 15.0, 8.1, 5.3 Hz, 1H), 2.44 (q, J= 8.4 Hz, 1H), 2.07¨ 1.76 (m, 3H), 1.68 ¨ 1.41 (m, 4H), 1.41 ¨ 1.14 (m, 7H), 0.57 (t, J= 7.2 Hz, 3H).
Example 110 (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate a F---\
NC N-N
\
N
N \
k ' N
N \-0 HN--µ

0 NC "
HO
Nr\N-N EDCI, DMAP, DCM N

_______________________________________________ k NI, k HN

OH
HN--\\'7 Synthesis of (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-acetamidophenyl) acetate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (171 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 145 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5 mL) and N, N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.133 g, 52% yield. MS
(m/z): [M+H] calcd for C28H29N703, 512.23; found, 512.3.1H NMR (400 MHz, DMSO-d6) .3 9.91 (s, 1H), 8.83 (d, J= 20.0 Hz, 2H), 8.41 (s, 1H), 7.75 (d, J= 3.7 Hz, 1H), 7.49 (d, J= 8.3 Hz, 2H), 7.18 ¨ 7.10 (m, 3H), 6.27 (s, 2H), 4.55 (td, J= 9.6, 4.2 Hz, 1H), 3.65 (s, 2H), 3.30 ¨ 3.15 (m, 2H), 2.48 ¨2.37 (m, 1H), 2.03 (s, 3H), 1.87¨ 1.76 (m, 1H), 1.66¨ 1.42 (m, 4H), 1.41 ¨ 1.15 (m, 3H).
Example 111 (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate NC "
o NC N-N
\
NC " 5õ 0 EDCI, DMAP, DCM
+ HO \ 0 N p OH

Synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-((tert-butoxycarbonyl) amino)-2-phenylacetate (R)-3-cyclopenty1-3-(4-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) propanenitrile (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), N-Boc-L-phenylglycine (189 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5mL) and N, N-dimethylformamide (0.3mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.153 g, 53.7% yield.
MS (m/z): [M+H] calcd for C31H35N704, 570.28; found, 570.2.1H NMR (400 MHz, DMSO-d6) .3 8.84 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.82 (d, J= 7.8 Hz, 1H), 7.66 (d, J= 3.7 Hz, 1H), 7.40 ¨ 7.19 (m, 5H), 7.09 (d, J= 3.8 Hz, 1H), 6.37 ¨ 6.22 (m, 2H), 5.19 (d, J= 7.8 Hz, 1H), 4.55 (td, J= 9.7, 4.2 Hz, 1H), 3.29 ¨ 3.15 (m, 2H), 2.45 ¨
2.34 (m, 1H), 1.88¨ 1.77 (m, 1H), 1.67¨ 1.40 (m, 4H), 1.39¨ 1.11 (m, 12H).
Example 112 Methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) 2-(4-isobutylphenyl) propanoate -o s-N-N
N \
N
N

S' 0' 0N
-S' 0' `N CN N-N
Lq) HO
N-N 0 EDCI, DMAP,DCM
0) N \
N N

HO
Synthesis of methyl (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) 2-(4-isobutylphenyl) propanoate 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pynolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (143 mg, 0.356 mmol), 4-dimethylamino pyridine (DMAP, 44 mg, 0.356 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 110 mg, 0.534 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 103 mg, 0.534 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.191 g, 91% yield. MS (m/z): [M+H] calcd for C301-135N704S, 590.25, found 590.3.1H NMR
(400 MHz, Chloroform-d) 8.85 (s, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 7.44 (d, J= 3.8 Hz, 1H), 7.09 (d, J=
8.1 Hz, 2H), 7.00 (d, J= 8.1 Hz, 2H), 6.71 (d, J= 3.8 Hz, 1H), 6.27 ¨6.17 (m, 2H), 4.63 (d, J= 9.2 Hz, 2H), 4.29 ¨4.22 (m, 2H), 3.70 (q, J= 7.1 Hz, 1H), 3.40 (s, 2H), 3.08 (q, J= 7.4 Hz, 2H), 2.38 (d, J= 7.2 Hz, 2H), 1.79 (dh, J= 13.5, 6.7 Hz, 1H), 1.48 ¨ 1.38 (m, 6H), 0.85 (d, J= 6.6 Hz, 6H).
Example 113 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1'-bipheny11-4-y1) propanoate 9, -S
N
N
o) (21,, -S
H
(:)µµ HO
-S
ON
H 0 N\
EDCI, DMAP,DCM N

Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 183 mg, 0.75 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.072 g, 24.2% yield. MS (m/z): [M+H] calcd for C31H36FN5045, 594.25; found, 594.1.1H NMR
(400 MHz, DMSO-d6) .3 8.16 (s, 1H), 7.54¨ 7.44 (m, 4H), 7.42¨ 7.35 (m, 2H), 7.29 (d, J= 3.7 Hz, 1H), 7.12 (d, J= 9.9 Hz, 2H), 6.90 (q, J= 5.0 Hz, 1H), 6.63 (d, J= 3.7 Hz, 1H), 6.17 (d, J=
2.1 Hz, 2H), 4.64 (s, 1H), 3.89 (q, J= 7.1 Hz, 1H), 3.15 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.07¨ 1.99 (m, 2H), 1.84 (dt, J=
11.8, 6.9 Hz, 1H), 1.75¨ 1.61 (m, 4H), 1.39 (d, J= 7.1 Hz, 3H), 1.36¨ 1.21 (m, 2H).
Example 114 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(3-phenoxyphenyl) propanoate (:),µ
.s Ho r\r\)Xr) o) HOrN--9µ
HO
H N kN' N

EDCLDMAP,DCM oi N \--OH Th Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(3-phenoxyphenyl) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 182 mg, 0.75 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.118 g, 39.9% yield. MS (m/z): [M+H] calcd for C311-137N505S, 592.25; found, 592.2.1H NMR (400 MHz, DMSO-d6) .3 8.22 (s, 1H), 7.42 (dd, J= 8.5, 7.3 Hz, 2H), 7.35 ¨7.28 (m, 2H), 7.19 (t, J= 7.4 Hz, 1H), 7.07 ¨6.85 (m, 6H), 6.68 (d, J= 3.7 Hz, 1H), 6.19 (s, 2H), 4.71 (s, 1H), 3.86 (q, J= 7.1 Hz, 1H), 3.21 (s, 3H), 3.01 (d, J= 6.2 Hz, 2H), 2.64 (d, J= 5.0 Hz, 3H), 2.10 (d, J= 12.9 Hz, 2H), 1.97 ¨ 1.82 (m, 1H), 1.73 (t, J= 5.3 Hz, 4H), 1.42¨ 1.27 (m, 5H).
Example 115 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate c),µ
H

-S
H
N
HO
,S
H
EDCI, DMAP,DCM. 0) OH

Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 185 mg, 0.75 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.073 g, 24.5% yield. MS (m/z): [M+H] calcd for C31H41N5055, 596.28; found, 596.2. 11-1 NMR (400 MHz, DMSO-d6) .3 8.15 (d, J= 1.9 Hz, 1H), 7.25 (d, J= 3.7 Hz, 1H), 7.07 (qd, J= 8.3, 2.9 Hz, 4H), 6.89 (q, J=
4.9 Hz, 1H), 6.62 (d, J= 3.8 Hz, 1H), 6.12 (d, J= 1.6 Hz, 2H), 4.65 (s, 1H), 3.74 (q, J= 7.0 Hz, 1H), 3.16 (s, 3H), 3.00 ¨ 2.80 (m, 3H), 2.59 (d, J= 5.0 Hz, 3H), 2.45 ¨2.16 (m, 3H), 2.05 (dddd, J= 14.5, 10.1, 8.5, 1.7 Hz, 3H), 1.93¨ 1.78 (m, 3H), 1.74 ¨ 1.60 (m, 5H), 1.48¨ 1.41 (m, 1H), 1.36¨ 1.21 (m, 5H).
Example 116 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate Th\l-S\n`
HO"N
N

CI

HO

N

LEDOLDMAP,DCM

NI-11\-OH N 0 CI
Synthesis of (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (170 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 277 mg, 0.75 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (8.5 mL) and dimethylformamide (0.3 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a light yellow solid, 0.136 g, 38.5% yield. MS (m/z): [M+H] calcd for C35H39C1N6065, 707.23; found,707Ø1H
NMR (400 MHz, DMSO-d6) .3 8.17 (s, 1H), 7.64 (s, 4H), 7.28 (d, J= 3.7 Hz, 1H), 7.01 ¨ 6.83 (m, 3H), 6.70 (dd, J
= 9.0, 2.6 Hz, 1H), 6.64 (d, J= 3.8 Hz, 1H), 6.17 (s, 2H), 4.67 (s, 1H), 3.80 (s, 2H), 3.70 (s, 3H), 3.17 (s, 3H), 2.96 (d, J= 6.2 Hz, 2H), 2.60 (d, J= 4.9 Hz, 3H), 2.14 (s, 3H), 2.06 (d, J=
12.8 Hz, 2H), 1.96¨ 1.80 (m, 1H), 1.77¨ 1.63 (m, 4H), 1.31 (p, J= 4.9, 4.3 Hz, 2H).
Example 117 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-(1-) oxoisoindolin -2-y1) phenyl) butanoate (:),µ
H N
Q. N
o OH
H
-S
N
H
'N 0 EDCI, DMAP,DCM
0) +

OH N

\--Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-(1-) oxoisoindolin -2-y1) phenyl) butanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (20 mg, 0.058 mmol), 4-dimethylamino pyridine (DMAP, 4 mg, 0.03 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 26 mg, 0.09 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 17 mg, 0.09 mmol) were dissolved in a mixed solvent of dichloromethane (0.5mL) and N, N-dimethylformamide (0.05 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.156 g, 48.4% yield. MS (m/z):
[M+H] calcd for C34H40N6055, 645.28; found,645.1 .1H NMR (400 MHz, DMSO-d6) .3 8.17 (s, 1H), 7.86 ¨ 7.75 (m, 3H), 7.68 (dd, J= 6.3, 1.2 Hz, 2H), 7.55 (ddd, J= 8.1, 6.3, 2.0 Hz, 1H), 7.34¨ 7.24 (m, 3H), 6.88 (q, J= 5.0 Hz, 1H), 6.62 (d, J= 3.8 Hz, 1H), 6.22 ¨ 6.08 (m, 2H), 4.99 (s, 2H), 4.64 (s, 1H), 3.55 (t, J = 7.6 Hz, 1H), 3.14 (s, 3H), 2.94 (d, J = 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.06¨ 1.91 (m, 3H), 1.89 ¨ 1.78 (m, 1H), 1.77¨ 1.61 (m, 5H), 1.33 ¨ 1.21 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H).
Example 118 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) benzoate c),µ
H N
%)1) HN

H N
HO
H 0=
ki\r N
EDCI, DMAP,DCM 0 HN

N \--OH HN
Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-((2, 3-dimethylphenyl) amino) benzoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (171 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 181 mg, 0.75 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in a mixed solvent of dichloromethane (8.5mL) and N, N-dimethylformamide (0.3 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a yellow solid, 0.096 g, 32.5% yield. MS (m/z):
[M+H] calcd for C31H38N6045, 591.27; found, 591.2.1H NMR (400 MHz, DMSO-d6) .3 9.07 (s, 1H), 8.21 (s, 1H), 7.73 (dd, J= 8.1, 1.6 Hz, 1H), 7.47 (dd, J= 8.8, 3.9 Hz, 1H), 7.32 (ddd, J= 8.6, 7.0, 1.7 Hz, 1H), 7.19¨ 7.03 (m, 3H), 6.90 (q, J= 4.9 Hz, 1H), 6.66 (ddd, J= 20.2, 9.1, 4.5 Hz, 3H), 6.41 (s, 2H), 4.68 (s, 1H), 3.22 ¨ 3.13 (m, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 4.9 Hz, 3H), 2.29 (s, 3H), 2.06 (d, J= 14.3 Hz, 5H), 1.92¨ 1.79 (m, 1H), 1.70 (h, J= 3.4 Hz, 4H), 1.38 ¨
1.19 (m, 2H).
Example 119 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-(4-isobutylphenyl) propanoate .s N,LN
o) HO

EDCI, DMAP,DCM,_ N N
m N

Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-(4-isobutylphenyl) propanoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (201 mg, 0.5 mmol), 4-dimethylamino pyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 123.6 mg, 0.6 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a white solid, 0.142 g, 51.1% yield. MS (m/z): [M+H] calcd for C29H411\15045, 556.29, found 556.21H
NMR (400 MHz, DMSO-d6) 8.15 (s, 1H), 7.24 (d, J= 3.8 Hz, 1H), 7.08 (d, J= 8.1 Hz, 2H), 7.01 (d, J=
8.0 Hz, 2H), 6.89 (q, J= 5.0 Hz, 1H), 6.61 (d, J= 3.7 Hz, 1H), 6.12 (s, 2H), 4.66 (s, 1H), 3.73 (q, J= 7.0 Hz, 1H), 3.15 (s, 3H), 2.95 (d, J= 6.2 Hz, 2H), 2.59 (d, J= 5.0 Hz, 3H), 2.37 (d, J= 7.1 Hz, 2H), 2.05 (d, J= 12.9 Hz, 2H), 1.91¨ 1.80 (m, 1H), 1.79¨ 1.64 (m, 5H), 1.37¨ 1.25 (m, 5H), 0.82 (d, J= 6.6 Hz, 6H).
Example 120 (4-(Methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl 2-((3-chloro-2-methylphenyl) amino) benzoate (:),µ
.S
N
H 0 õN
N
N' N
0 *
HN
CI

Ciµµ

\\
=
HO N
FleC(:) 0Nv N
N-. EDCI, DMAP,DCIVI
HN
0 *
N
N CI HN
CI
Synthesis of (4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methyl 2-((3-chloro-2-methylphenyl) amino) benzoate 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methyl methanesulfonamide (200 mg, 0.58 mmol), 4-dimethylamino pyridine (DMAP, 35 mg, 0.29 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 230 mg, 0.88 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 168 mg, 0.88 mmol) were dissolved in a mixed solvent of dichloromethane (10 mL) and N, N-dimethylformamide (0.2 mL), and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 150: 1 to 50: 1) to give the title compound as a yellow solid, 0.137 g, 44.9% yield. MS (m/z):
[M+H] calcd for C301-135C1N6045, 611.21; found, 611.2.1H NMR (400 MHz, DMSO-d6) .3 9.18 (s, 1H), 8.26 (s, 1H), 7.81 (dd, J= 8.2, 1.5 Hz, 1H), 7.51 (d, J= 3.7 Hz, 1H), 7.43 (td, J= 7.7, 7.1, 1.7 Hz, 1H), 7.40¨ 7.20 (m, 3H), 6.95 (q, J= 5.0 Hz, 1H), 6.84 ¨
6.73 (m, 3H), 6.47 (s, 2H), 4.74 (s, 1H), 3.24 (s, 3H), 3.01 (d, J= 6.2 Hz, 2H), 2.65 (d, J= 4.9 Hz, 3H), 2.29 (s, 3H), 2.11 (dd, J= 10.1, 5.0 Hz, 2H), 2.00¨ 1.86 (m, 1H), 1.74 (d, J= 9.5 Hz, 4H), 1.36 (q, J = 10.0, 7.2 Hz, 2H).
Example 121 4-04-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide -o o---s s q) CN
NL
N¨N
N \
N
N ) ...0 .S' 0' s CN
f\14. j \
,' \

' = CN
r4) HO 0 -=%=-= N \

+ Nr\ DIAD,PPh3 N¨N N' N, \ '''-= r- __ .-N
H THF
SõN'' HO' 1IXINIH
Synthesis of 44(4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (piroxicam, 103 mg, 0.312 mmol) and triphenylphosphine (PPh3, 164 mg, 0.624 mmol) were added to tetrahydrofuran (3 mL) under nitrogen. After cooling to -10 C, diisopropyl azodicarboxylate (DIAD, 95 mg, 0.468 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature naturally, 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitile (150 mg, 0.374 mmol) was added and the stirring was continued. The reaction was monitored by TLC. After complete exhaust of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9:
1) to give the title compound as a yellow solid, 0.012 g, 5.3% yield. MS (m/z): [M+H] calcd for C32H30N100652, 715.18, found 715.2.1H NMR (400 MHz, Chloroform-d) .3 8.79 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.94 ¨ 7.85 (m, 2H), 7.76 ¨ 7.68 (m, 2H), 7.51 (d, J= 8.3 Hz, 1H), 7.38 ¨ 7.32 (m, 1H), 7.24 (d, J= 3.8 Hz, 1H), 6.92 ¨ 6.86 (m, 1H), 6.60 (d, J= 3.8 Hz, 1H), 6.05 (s, 2H), 4.56 (d, J= 9.3 Hz, 2H), 4.18 (d, J= 9.3 Hz, 2H), 3.35 (s, 2H), 3.08 ¨2.96 (m, 5H), 1.36 (t, J= 7.4 Hz, 3H).
Example 122 4-04-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-2-methyl-N-(5-methylthiazol-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide - s-o- \ CN
ILID\
N-N
\
N
N \
kN N\
/
0 0 11"-N S
,N H
's\O 6 -.S' 0' CN
-3' 0' CN
NLI) N-N DIAD,PPh3 N \
N
N H
S' THF
N \ 0 0 N N S

Synthesis of 4-04-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methoxy)-2-methyl-N-(5-methylthiazol-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(5-methylthiazol-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (meloxicam, 147 mg, 0.42 mmol) and triphenylphosphine (PPh3, 137 mg, 0.52 mmol) were added to tetrahydrofuran (2.8 mL) under nitrogen. Diisopropyl azodicarboxylate (DIAD, 92 mg, 0.45 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature naturally. 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pyrrolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitrile (140 mg, 0.35 mmol) was added and the stirring was continued.
The reaction was monitored by TLC. After complete exhaust of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9: 1) to give the title compound as a yellow solid, 0.005 g, 1.9% yield. MS (m/z): [M+H] calcd for C311-130N100653, 735.15, found 735.1.1H NMR (400 MHz, DMSO-d6) .3 14.61 (s, 1H), 8.94 (s, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.02 (d, J= 7.7 Hz, 1H), 7.88¨ 7.78 (m, 3H), 7.73 (d, J= 3.7 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J= 3.7 Hz, 1H), 5.62 (s, 2H), 4.60 (d, J= 9.1 Hz, 2H), 4.24 (dd, J=
9.1, 2.4 Hz, 2H), 3.69 (d, J= 2.7 Hz, 2H), 3.27 ¨ 3.20 (m, 2H), 2.85 (s, 3H), 2.32 (s, 3H), 1.27¨ 1.20 (m, 3H).
Example 123 (3S, 4R)-3-ethyl-4-(3-((S)-2-(4-isobutylphenyl) propanoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F
N

F F

EDCI,DMAP,DCM (-T
F F 1\e N z N 0 ( Synthesis of (3S, 4R)-3-ethyl-4-(3-((S)-2-(4-isobutylphenyl) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 338 mg, 1 mmol), 4-dimethylamino pyridine (DMAP, 122 mg, 1 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid ((S)-(+)-ibuprofen, 247 mg, 1.2 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.05 g, 17.6% yield. MS (m/z): [M+H] calcd for C301-135P3N602, 569.28; found, 569.3.41 NMR (400 MHz, DMSO-d6) 8.88 (s, 1H), 8.04 (d, J= 4.2 Hz, 1H), 7.63 (s, 1H), 7.37¨ 7.29 (m, 2H), 7.19 ¨ 7.04 (m, 3H), 6.97 (t, J= 6.3 Hz, 1H), 5.99 (q, J = 6.9 Hz, 1H), 4.34 (q, J = 6.5 Hz, 1H), 3.91 ¨ 3.71 (m, 4H), 3.71 ¨ 3.61 (m, 1H), 3.25 (dd, J =
10.2, 5.7 Hz, 1H), 2.38 (dd, J= 23.9, 7.1 Hz, 3H), 1.83 ¨ 1.72 (m, 1H), 1.59 (d, J= 6.9 Hz, 3H), 1.07 ¨0.93 (m, 1H), 0.92¨ 0.80 (m, 7H), 0.60 (t, J= 7.3 Hz, 3H).
Example 124 (3S, 4R)-3-ethyl-4-(3-(2-(4-isobutylphenyl) propanoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F
N
<7 -1 (-T
EDCI,DMAP,DCM F F
F F
1\1..õ_õ,N 0 Synthesis of (3S, 4R)-3-ethyl-4-(3-(2-(4-isobutylphenyl) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 54 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.097 g, 34.1% yield. MS (m/z): [M+H] calcd for C301-135P3N602, 569.28; found, 569.3.1H
NMR (400 MHz, Chloroform-d) .3 8.79 (s, 1H), 7.93 (t, J= 3.7 Hz, 1H), 7.52 (d, J= 4.3 Hz, 1H), 7.36 ¨ 7.26 (m, 2H), 7.06 ¨ 6.94 (m, 3H), 6.78 (dd, J= 4.2, 1.5 Hz, 1H), 5.98 (qd, J= 6.9, 3.4 Hz, 1H), 4.70 (t, J= 6.5 Hz, 1H), 4.08 (dt, J= 12.2, 6.2 Hz, 1H), 3.98 ¨3.61 (m, 4H), 3.29 (d, J= 8.3 Hz, 1H), 2.62 ¨ 2.46 (m, 1H), 2.31 (dd, J=
9.0, 7.2 Hz, 2H), 1.82 ¨1.67 (m, 1H), 1.61 (dd, J= 6.9, 1.2 Hz, 3H), 1.27¨ 1.09 (m, 1H), 0.87 ¨ 0.73 (m, 7H), 0.66 (dt, J= 10.3, 7.3 Hz, 3H).
Example 125 (3S, 4R)-3-ethyl-4-(3-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F

OH F

EDCI,DMAP,DCM NN

N N
Synthesis of (3S, 4R)-3-ethyl-4-(3-(2-(2-fluoro-[1, 1 '-bipheny11-4-y1) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(2-fluoro-4-biphenyl) propanoic acid (flurbiprofen, 64 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.03 g, 9.9% yield. MS (m/z): [M+H] calcd for C32H30F4N602, 607.24; found, 607.3.1H
NMR (400 MHz, DMSO-d6) 8.93 (d, J= 2.0 Hz, 1H), 8.10 (dd, J= 4.2, 2.5 Hz, 1H), 7.65 (d, J= 6.9 Hz, 1H), 7.58 ¨ 7.32 (m, 9H), 6.98 (t, J=
5.8 Hz, 1H), 6.09 (p, J= 6.9 Hz, 1H), 4.36 (s, 1H), 3.95 ¨3.74 (m, 4H), 3.69 (dt, J= 10.7, 6.1 Hz, 1H), 3.26 (dd, J
= 10.2, 5.3 Hz, 1H), 3.09 (td, J= 7.3, 4.7 Hz, 1H), 1.66 (d, J= 6.9 Hz, 3H), 1.12 ¨ 0.96 (m, 1H), 0.93 ¨0.75 (m, 1H), 0.63 (dt, J= 10.2, 7.3 Hz, 3H).
Example 126 (3R, 45)-3-(3-(2-(3-benzoylphenyl) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F
(-T

F-/F_ OH F F
N
(--T
F H

,N + EDCI,DMAP,DCM NI-The F F
N . 0 el. :
N NI' Synthesis of (3R, 4S)-3-(3-(2-(3-benzoylphenyl) propanoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine-l-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 67 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.13 g, 84.4% yield. MS (m/z): [M+H] calcd for C33H31F3N603, 617.24; found, 617.2.1H
NMR (400 MHz, DMSO-d6) .3 8.80 (d, J= 5.8 Hz, 1H), 8.07 (dd, J= 4.3, 1.8 Hz, 1H), 7.85 ¨7.71 (m, 2H), 7.71 ¨7.57 (m, 5H), 7.57 ¨ 7.47 (m, 3H), 7.45 (d, J= 4.3 Hz, 1H), 6.97 (t, J= 6.3 Hz, 1H), 6.09 (p, J= 7.0 Hz, 1H), 4.35 (q, J= 6.5 Hz, 1H), 3.90 ¨
3.63 (m, 5H), 3.26 (dt, J= 10.1, 5.1 Hz, 1H), 2.58 ¨ 2.49 (m, 1H), 1.64 (dd, J= 7.0, 2.1 Hz, 3H), 1.03 (dp, J=
20.6, 7.0 Hz, 1H), 0.81 (s, 1H), 0.61 (dt, J= 14.6, 7.3 Hz, 3H).
Example 127 (3R, 45)-3-(3-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide ,.)\----N
F--7CH"
-F F
r:t N re H CI
N
CI

E

F F

H ci EDCI,DMAP,DCM .. eT
N ,N
F F N
N

H CI
CI
Synthesis of (3R, 4S)-3-(3-(2-(2-((2, 6-dichlorophenyl) amino) phenyl) acetyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(2, 6-dichloroanilino) phenylacetic acid (diclofenac, 78 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.011 g, 6.6% yield. MS (m/z): [M+H] calcd for C311-128C12F3N702, 658.16; found, 658.1.1H NMR (400 MHz, Chloroform-d) .3 8.85 (s, 1H), 8.00 (d, J = 4.1 Hz, 1H), 7.58 (s, 1H), 7.38 (dd, J = 7.5, 1.5 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.08 (td, J = 7.8, 1.6 Hz, 1H), 6.93 ¨6.85 (m, 4H), 6.52 (d, J = 8.0 Hz, 1H), 5.11 (s, 2H), 4.69 (t, J = 6.3 Hz, 1H), 4.15 (q, J = 6.1 Hz, 1H), 3.89 (if, J = 15.6, 8.6 Hz, 4H), 3.72 ¨
3.66 (m, 1H), 3.30 (t, J = 8.2 Hz, 1H), 2.57 (dd, J = 11.0, 6.3 Hz, 1H), 1.27¨ 1.14 (m, 1H), 0.84 ¨ 0.77 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H).
Example 128 (3S, 4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl) propanoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F
NN
N N-O
* o F OH F N N
0 EDCI,DMAP,DCM CT
F FNN

41, o Synthesis of (3S, 4R)-3-ethyl-4-(3-(2-(3-phenoxyphenyl) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-tifluoroethyl) pyrrolidine-l-carboxamide (EDCI, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(3-phenoxyphenyl) propanoic acid (fenoprofen, 64 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (Upadacitinib, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.101 g, 66.8% yield. MS (m/z): [M+H] calcd for C32H31F3N603, 605.24; found, 605.2.1H
NMR (400 MHz, DMSO-d6) 8.74 (d, J= 6.8 Hz, 1H), 8.04 (t, J= 3.9 Hz, 1H), 7.65 (d, J= 6.7 Hz, 1H), 7.49 ¨ 7.26 (m, 4H), 7.23 ¨6.80 (m, 7H), 5.97 (p, J = 6.8 Hz, 1H), 4.38 ¨4.30 (m, 1H), 3.92 ¨ 3.75 (m, 3H), 3.69 (dd, J = 8.4, 6.0 Hz, 2H), 3.26 (dt, J
= 10.3, 6.7 Hz, 1H), 2.52¨ 2.48 (m, 1H), 1.62¨ 1.55 (m, 3H), 1.07 ¨ 0.98 (m, 1H), 0.90 ¨ 0.78 (m, 1H), 0.63 (td, J
= 7.4, 3.7 Hz, 3H).
Example 129 (3R, 45)-3-(3-(2-((2, 3-dimethylphenyl) amino) benzoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F
NN
41k 0 NH

(-1 0 EDCI,DMAP,DCM NN
NN F F NH N
41k 0 NH
Synthesis of (3R, 45)-3-(3-(2-((2, 3-dimethylphenyl) amino) benzoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-((2, 3-dimethylphenyl) amino) benzoic acid (mefenamic acid, 64 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a yellow solid, 0.012 g, 85.5% yield. MS (m/z): [M+H] calcd for C32H32F3N702, 604.264; found, 604.2.1H
NMR (400 MHz, DMSO-d6) .3 8.65 (s, 1H), 8.57 (s, 1H), 7.77 (d, J= 3.9 Hz, 1H), 7.61 (s, 1H), 7.48 ¨7.36 (m, 3H), 7.09 ¨ 6.95 (m, 4H), 6.88 ¨
6.74 (m, 2H), 4.38 (t, J= 6.5 Hz, 1H), 3.92 ¨ 3.70 (m, 5H), 3.31 ¨3.25 (m, 1H), 2.63 ¨2.52 (m, 1H), 2.23 (s, 3H), 2.00 (s, 3H), 1.19¨ 1.04 (m, 1H), 0.90 ¨ 0.82 (m, 1H), 0.68 (t, J= 7.3 Hz, 3H).
Example 130 (3R, 4S)-3-(3-(2-((3-chloro-2-methylphenyl) amino) benzoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide N Nj F--7C-H)\---- F F
N,,,,,,N
(f N--"'N

NH
CI

F-7r-HN\--N

OH e_iNN
)\--N
0 EDCI,DMAP,DCM N"---'N.>"
F F +
N NH
...- * 0 N /
(---f git NH
H CI
41, ci Synthesis of (3R, 4S)-3-(3-(2-((3-chloro-2-methylphenyl) amino) benzoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-((3-chloro-2-methylphenyl) amino) benzoic acid (tolfenamic acid, 68 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a yellow solid, 0.09 g, 29.7% yield. MS (m/z): [M+H] calcd for C311-129C1F3N702, 624.20; found, 624.2.1H NMR (400 MHz, DMSO-d6) .3 8.61 (s, 1H), 8.25 (s, 1H), 7.67 ¨ 7.58 (m, 1H), 7.56 ¨ 7.44 (m, 2H), 7.36 (d, J= 4.2 Hz, 1H), 7.22 (d, J= 4.9 Hz, 1H), 7.10 ¨6.85 (m, 5H), 6.81 ¨6.75 (m, 1H), 4.36 (d, J= 6.6 Hz, 1H), 3.96¨
3.65 (m, 5H), 3.34¨ 3 .21(m, 1H), 2.62 ¨ 2.53 (m, 1H), 1.96 (s, 3H), 1.16¨ 1.01 (m, 1H), 0.93 ¨0.76 (m, 1H), 0.72 ¨ 0.66 (m, 3H).
Example 131 (3S, 4R)-3-ethy1-4-(3-((S)-2-(6-) methoxynaphthalen -2-y1) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F-2CH"
F F
NN
N

OH F

EDCI,DMAP,DCM

Synthesis of (3S, 4R)-3-ethy1-4-(3-((S)-2-(6-) methoxynaphthalen -2-y1) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), (S)--(+)-2-(6-methoxy-2-naphthyl) propanoic acid (Naproxen, 60 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.028 g, 18.9% yield. MS (m/z): [M+H] calcd for C311-131P3N603, 593.24; found, 593.2.1H
NMR (400 MHz, DMSO-d6) 8.92 (s, 1H), 8.08 (d, J= 4.2 Hz, 1H), 7.91 ¨7.68 (m, 3H), 7.63 (s, 1H), 7.57 (dd, J= 8.5, 1.8 Hz, 1H), 7.43 ¨7.39 (m, 1H), 7.25 (d, J= 2.6 Hz, 1H), 7.12 (dd, J= 9.0, 2.6 Hz, 1H), 6.96 (t, J=
6.2 Hz, 1H), 6.13 (q, J= 6.9 Hz, 1H), 4.33 (d, J= 6.7 Hz, 1H), 3.97¨ 3.72 (m, 7H), 3.65 (dd, J= 10.3, 6.7 Hz, 1H),3.24 (dd, J= 10.3, 5.7 Hz, 1H), 2.53 ¨2.42 (m, 1H), 1.68 (d, J= 6.9 Hz, 3H), 1.03 ¨0.92 (m, 1H), 0.89 ¨ 0.71 (m, 1H), 0.57 (t, J= 7.3 Hz, 3H).
Example 132 (3S, 4R)-3-ethyl-4-(3-(2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F
N
C-f OH
N
EDCI,DMAP,DCM NN

N N
N

Synthesis of (3S, 4R)-3-ethyl-4-(3-(2-(4-((2-oxocyclopentyl) methyl) phenyl) propanoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl) phenyl] propanoic acid (loxoprofen, 65 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.066 g, 43.4% yield. MS (m/z): [M+H] calcd for C32H35P3N603, 609.27, found 609.3.1H
NMR (400 MHz, DMSO-d6) 8.88 (d, J= 0.9 Hz, 1H), 8.04 (t, J= 3.9 Hz, 1H), 7.63 (d, J= 7.0 Hz, 1H), 7.44 ¨ 7.30 (m, 3H), 7.22 ¨ 7.07 (m, 2H), 6.97 (t, J= 6.3 Hz, 1H), 6.00 (p, J= 7.0 Hz, 1H), 4.34 (d, J= 6.2 Hz, 1H), 3.96 ¨ 3.72 (m, 4H), 3.67 (ddd, J
= 10.9, 6.7, 4.6 Hz, 1H), 3.25 (dt, J= 10.3, 5.1 Hz, 1H), 2.93 ¨2.84 (m, 1H), 2.56 ¨ 2.51 (m, 1H), 2.43 ¨2.26 (m, 2H), 2.20 (dd, J= 18.6, 8.4 Hz, 1H), 2.12¨ 1.96 (m, 1H), 1.91 ¨ 1.73(m, 2H), 1.72¨ 1.50 (m, 4H), 1.48¨ 1.36 (m, 1H), 1.02 (ddq, J= 19.7, 12.8, 7.1, 6.6 Hz, 1H), 0.80 (ddt, J= 16.9, 13.8, 6.5 Hz, 1H), 0.62 (dt, J= 10.3, 7.3 Hz, 3H).
Example 133 (3R, 4S)-3-(3-(2-(1-(4-Chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F F
N

CI
F-7rri OH F F
o N N

EDCI,DMAP,DCM N

N N

NN
CI
CI
Synthesis of (3R, 4S)-3-(3-(2-(1-(4-Chlorobenzoy1)-5-methoxy-2-methyl-1H-indol-3-y1) acetyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 1-(4-chlorobenzoy1)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 95 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a light yellow solid, 0.139 g, 77.3% yield. MS (m/z): [M+H] calcd for C36H33C1F3N704, 720.22, found 720.1.1H NMR (400 MHz, DMSO-d6) .3 8.95 (s, 1H), 8.10 (d, J= 4.1 Hz, 1H), 7.75 ¨7.63 (m, 5H), 7.50 (d, J= 4.2 Hz, 1H), 7.18 (d, J= 2.6 Hz, 1H), 7.00 (dd, J = 7.7, 5.0 Hz, 2H), 6.73 (dd, J = 9.0, 2.5 Hz, 1H), 5.06 (d, J = 4.3 Hz, 2H), 4.41 (q, J = 6.4 Hz, 1H), 3.93 ¨ 3.83 (m, 3H), 3.83 ¨ 3.67 (m, 5H), 3.27 (dd, J= 10.2, 5.9 Hz, 1H), 2.58 (s, 1H), 2.27 (s, 3H), 1.07 (ddd, J= 12.8, 7.4, 4.9 Hz, 1H), 0.82 (ddd, J= 13.3, 10.0, 7.0 Hz, 1H), 0.65 (t, J= 7.3 Hz, 3H).

Example 134 (3R, 4S)-3-(3-(2-(4-acetamidophenyl) acetyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide NN
F F

OH >\--N1 F-7(10 F F
N,N
0 EDCI,DMAP,DCM
F F

N
0)---NH
Synthesis of (3R, 45)-3-(3-(2-(4-acetamidophenyl) acetyl)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(4-acetamidophenyl) acetic acid (actarit, 51 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.082 g, 59% yield. MS (m/z): [M+H] calcd for C27F128F3N703, 556.22, found 556.1.1H NMR
(400 MHz, DMSO-d6) 9.93 (s, 1H), 8.89 (s, 1H), 8.06 (d, J = 4.2 Hz, 1H), 7.65 (s, 1H), 7.57 ¨
7.48 (m, 2H), 7.46 (d, J = 4.1 Hz, 1H), 7.35 ¨7.27 (m, 2H), 6.99 (t, J= 6.4 Hz, 1H), 4.88 (d, J= 3.6 Hz, 2H), 4.39 (q, J= 6.7 Hz, 1H), 3.92 ¨ 3.74 (m, 4H), 3.70 (dd, J= 10.2, 6.7 Hz, 1H), 3.26 (dd, J= 10.2, 5.9 Hz, 1H), 2.56 (s, 1H), 2.03 (s, 3H), 1.06 (ddd, J= 12.9, 7.7, 5.2 Hz, 1H), 0.89 ¨ 0.73 (m, 1H), 0.64 (t, J= 7.3 Hz, 3H).
Example 135 (3R, 45)-3434241, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indol -1-y1) acetyl)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide N
r-NH

H
NN

HO
F H H 0 EDCI,DMAP,DCM F NH
F F + F F N

Synthesis of (3R, 4S)-3-(3-(2-(1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano [3, 4-b] indol -1-y1) acetyl)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-4-ethyl-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pynolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 1, 8-diethyl-1, 3, 4, 9-tetrahydropyran [3, 4-h] indole -1-acetic acid (etodolac, 76 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.108 g, 66.5% yield. MS (m/z): [M+H] calcd for C34F138F3N703, 650.30, found 650.3.1H
NMR (400 MHz, DMSO-d6) 10.55 (d, J= 10.5 Hz, 1H), 8.79 (s, 1H), 8.01 (t, J= 4.1 Hz, 1H), 7.62 (d, J=
2.5 Hz, 1H), 7.40 (d, J= 4.2 Hz, 1H), 7.22 (td, J= 7.5, 1.6 Hz, 1H), 6.99 (t, J= 6.3 Hz, 1H), 6.89 (td, J= 7.4, 5.1 Hz, 2H), 4.61 (dd, J= 47.7, 14.4 Hz, 1H), 4.36 (d, J= 6.7 Hz, 1H), 4.13 (dd, J= 41.9, 14.4 Hz, 1H), 3.95 ¨ 3.74 (m, 6H), 3.69 (dd, J= 10.3, 6.9 Hz, 1H), 3.26 (dd, J= 10.3, 5.8 Hz, 1H), 2.90 ¨ 2.81 (m, 2H), 2.60 (q, J= 4.7 Hz, 2H), 2.24 ¨ 2.14 (m, 2H), 1.25 (td, J
= 7.4, 2.7 Hz, 4H), 1.10¨ 1.00 (m, 1H), 0.82 (dtd, J= 13.7, 7.0, 3.4 Hz, 1H), 0.71 (q, J= 7.1 Hz, 3H), 0.64 (td, J
= 7.3, 2.8 Hz, 3H).
Example 136 2-(8-((3R, 45)-4-ethy1-14(2, 2, 2-trifluoroethyl) carbamoyl) pyrrolidin -3-y1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazine -3-carbonyl) phenylacetate F F
N
= 0 +
OH N N
F
= 7\ H * ___ EDCI,DMAP,DCM F F F - 0 N N
r\L
C:t 0 = 0 Synthesis of 2-(8-((3R, 45)-4-ethy1-1-((2, 2, 2-trifluoroethyl) carbamoyl) pyrrolidin -3-y1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazine -3-carbonyl) phenylacetate (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-tifluoroethyl) pyrrolidine-1-carboxamide (EDCI, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-acetoxy benzoic acid (aspirin, 47.5 mg, 0.264 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (Upadacitinib, 73 mg, 0.377 mmol) was dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.025 g, 18.4% yield. MS (m/z):
[M+H] calcd for C26H25P3N604, 543.19, found 543.1.1H NMR (400 MHz, DMSO-d6) .3 8.56 (s, 1H), 7.85 (d, J= 4.2 Hz, 1H), 7.78 ¨7.71 (m, 2H), 7.60 (s, 1H), 7.51 ¨7.44 (m, 2H), 7.34 (dd, J= 8.1, 1.0 Hz, 1H), 6.99 (t, J=
6.3 Hz, 1H), 4.43 ¨4.35 (m, 1H), 3.92 ¨ 3.75 (m, 4H), 3.70 (dd, J= 10.2, 6.9 Hz, 1H), 3.27 ¨ 3.20 (m, 1H), 2.62 ¨ 2.49 (m, 1H), 1.89 (s, 3H), 1.08 (ddd, J= 12.9, 7.4, 4.9 Hz, 1H), 0.83 ¨ 0.75 (m, 1H), 0.64 (t, J= 7.3 Hz, 3H).
Example 137 Tert-butyl ((S)-2-(8-((3R, 45)-4-ethy1-14(2, 2, 2-trifluoroethyl) carbamoyl) pyrrolidin -3-y1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -3-y1)-2-oxo-1-phenethyl) carbamate F
F F
N
N
I.

1\1)\---N

N N
OH EDCI,DMAP,DCM F F
F F
N + 0 0 NThe 0 0 Synthesis of tert-butyl ((S)-2-(8-((3R, 45)-4-ethy1-1-((2, 2, 2-trifluoroethyl) carbamoyl) pyrrolidin -3-y1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -3-y1)-2-oxo-1-phenethyl) carbamate (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-tifluoroethyl) pynolidine-l-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), N-Boc-L-phenylglycine (66 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.088 g, 57.4% yield. MS (m/z):
[M+H] calcd for C301-134P3N704, 614.26, found 614.2.1H NMR (400 MHz, DMSO-d6) .3 8.89 (s, 1H), 8.07 (t, J= 4.2 Hz, 1H), 7.99 (dd, J= 7.5, 4.5 Hz, 1H), 7.67 ¨ 7.24 (m, 8H), 6.97 (td, J= 6.3, 2.3 Hz, 1H), 4.37 ¨ 4.29 (m, 1H), 3.91 ¨3.72 (m, 4H), 3.67 (dt, J
= 10.3, 6.4 Hz, 1H), 3.28 ¨ 3.18 (m, 1H), 2.52 ¨ 2.43 (m, 1H), 1.40 (d, J= 2.5 Hz, 9H), 1.05 ¨0.92 (m, 1H),0.88 ¨
0.68 (m, 1H), 0.62 (dt, J= 14.5, 7.3 Hz, 3H).
Example 138 (3S, 4R)-3-ethy1-4-(3-(2-(4-(1-) oxoisoindolin -2-y1) phenyl) butanoy1)-3H-imidazo [1, 2-a] pyrrolo [2, 3-e]
pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide F
F F
NN

OH F F

EDCI,DMAP,DCM NN

Synthesis of (3S, 4R)-3-ethy1-4-(3-(2-(4-(1-) oxoisoindolin -2-y1) phenyl) butanoy1)-3H-imidazo [1, 2-a]
pyrrolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pyrrolidine -1-carboxamide (3S, 4R)-3-ethyl-4-(3H-imidazo [1, 2-a] pynolo [2, 3-e] pyrazin -8-y1)-N-(2, 2, 2-trifluoroethyl) pynolidine -1-carboxamide (Upadacitinib, 100 mg, 0.25 mmol), 4-dimethylamino pyridine (DMAP, 3 mg, 0.025 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 78 mg, 0.264 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 73 mg, 0.377 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 25: 1) to give the title compound as a white solid, 0.145 g, 88.2% yield. MS (m/z): [M+H] calcd for C35H34P3N703, 658.27, found 658.2.1H
NMR (400 MHz, DMSO-d6) 8.93 (d, J= 1.8 Hz, 1H), 8.07 (dd, J= 7.3, 4.1 Hz, 1H), 7.91 ¨ 7.80 (m, 2H), 7.75 (dd, J= 7.6, 3.0 Hz, 1H), 7.71 ¨
7.59 (m, 3H), 7.58 ¨7.46 (m, 3H), 7.41 (t, J= 4.7 Hz, 1H), 6.96 (td, J= 6.3, 2.1 Hz, 1H), 5.86 (t, J= 7.4 Hz, 1H), 4.96 (d, J= 6.1 Hz, 2H), 4.37 ¨ 4.29 (m, 1H), 3.91 ¨ 3.73 (m, 4H), 3.67 (dt, J= 10.2, 6.4 Hz, 1H), 3.25 (dd, J=
10.3, 5.8 Hz, 1H), 2.56 ¨ 2.49 (m, 1H), 2.34 ¨ 2.19 (m, 1H), 1.94 (dtd, J=
12.8, 7.5, 4.7 Hz, 1H), 1.12 ¨ 0.99 (m, 1H), 0.95 (td, J= 7.3, 5.7 Hz, 3H), 0.80 (ddd, J= 16.9, 14.2, 7.4 Hz, 1H), 0.62 (dt, J= 17.9, 7.3 Hz, 3H).
Example 139 3-((35, 4R)-6-(7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile , _____________ C

OH

EDCI,DMAP,DCM

Synthesis of 3-((35, 4R)-6-(7-(2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile 3-((3S, 4R)-3-methyl-6-(7H-pyrrolo [2, 3-d] pyrimidin 6-diazaspiro [3.4] oct-1-y1)-3-oxopropanenitrile (Delgocitinib, 75 mg, 0.24 mmol), 4-dimethylamino pyridine (DMAP, 30 mg, 0.24 mmol), 2-(4-isobutylphenyl) propanoic acid (ibuprofen, 65 mg, 0.31 mmol) and 1(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC1, 70 mg, 0.36mm01) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:
1 to 10: 1) to give the title compound as a white solid, 0.081 g, 67.7% yield. MS (m/z): [M+H] calcd for C29H341\1602, 499.27, found 499.2.1H NMR (400 MHz, DMSO-d6) .3 8.37 (s, 1H), 7.67 (d, J= 4.1 Hz, 1H), 7.31 (d, J= 8.1 Hz, 2H), 7.07 (d, J
= 8.0 Hz, 2H), 6.90 (d, J= 4.1 Hz, 1H), 6.10 (q, J= 6.8 Hz, 1H), 4.20 ¨ 4.06 (m, 2H), 4.04 ¨ 3.24 (m, 3H), 3.68 (d, J= 3.3 Hz, 2H), 3.65 ¨3.53 (m, 1H), 2.72 ¨ 2.55 (m, 2H), 2.36 (d, J= 7.1 Hz, 2H), 2.20 (s, 1H), 1.82¨ 1.75 (m, 1H), 1.54 (d, J= 6.9 Hz, 3H), 1.13 (d, J= 7.0 Hz, 3H), 0.82 (d, J= 6.6 Hz, 6H).
Example 140 3-((35, 4R)-6-(7-((S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile N
jN
N

N, 0 OH

EDCI,DMAP,DCM e-Ttr,11 Synthesis of 3-((35, 4R)-6-(7-((S)-2-(4-isobutylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile 3-((3S, 4R)-3-methyl-6-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropaneni true (Delgocitinib, 75 mg, 0.24 mmol), 4-dimethylamino pyridine (DMAP, 30 mg, 0.24 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid((S)-(+)-ibuprofen , 65 mg, 0.3 1 mmol) and 1-(3-dimethylaminopropy1)-3-e thylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36mm01) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was dil uted with dichloromethane and washed with water and saturated salt water solution. The organic layer w as dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatogaph y (dichloromethane/methanol = 30: 1 to 10: 1) to give the title compound as a white solid, 0.071 g, 59.
4% yield. MS (m/z): [M+H] calcd for C29H341=1602, 499.27, found 499.3.1H NMR
(400 MHz, DMSO-d6) .3 8.37 (s, 1H), 7.67 (d, J = 4.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 4.1 Hz, 1H), 6.10 (q, J = 6.8 Hz, 1H), 4.20 ¨ 4.05 (m, 2H), 4.04 ¨
3.24 (m, 3H), 3.68 (d, J
= 3.3 Hz, 2H), 3.65 ¨ 3.53 (m, 1H), 2.73 ¨ 2.55 (m, 2H), 2.36 (d, J = 7.1 Hz, 2H), 2.20 (s, 1H), 1.7 7 (hept, J = 6.8 Hz, 1H), 1.54 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 6.6 Hz, 6 H).
Example 141 3-((35, 4R)-6-(74(S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile Si (N

N.
OH
O
< EDCI,DMAP,DCM

Ntri Synthesis of 3-((3S, 4R)-6-(74(S)-2-(6-methoxynaphthalen-2-y1) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile 3-((3S, 4R)-3-methyl-6-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1, 6-diazaspiro [3.4] oct-1-y1)-3-oxopropanenitrile (Delgocitinib, 75 mg, 0.24 mmol), 4-dimethylamino pyridine (DMAP, 30 mg, 0.24 mmol), (S)--(+)-2-(6-methoxy-2-naphthyl) propanoic acid (Naproxen, 70 mg, 0.31 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30: 1 to 10: 1) to give the title compound as a white solid, 0.013 g, 10.3% yield. MS (m/z): [M+H] calcd for C301-130N603, 523.24, found 523.2.1H
NMR (400 MHz, Chloroform-d) 8.38 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.67 ¨ 7.56 (m, 2H), 7.51 (dd, J =
8.6, 1.8 Hz, 1H), 7.40 ¨ 7.35 (m, 1H), 7.08 ¨ 6.98 (m, 2H), 6.53 (d, J = 4.2 Hz, 1H), 6.19 (q, J = 6.9 Hz, 1H), 4.30 ¨ 3.91 (m, 2H), 3.82 (d, J = 13.5 Hz, 5H), 3.69 (s, 1H), 3.63 ¨ 3.57 (m, 2H), 3.20 ¨ 3.05 (m, 1H), 2.84 ¨ 2.74 (m, 1H), 2.63 (p, J = 7.6, 7.2 Hz, 1H), 2.10¨ 1.99 (m, 1H), 1.21 ¨ 1.08 (m, 3H), 0.85 ¨0.75 (m, 3H).
Example 142 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-2-methyl-N-(5-methylthiazol-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide A CN
N¨ N

N S
0.1\1 H

N' NNCN rCN
1\1 OH 0 In DIAD,PPh3 N S

1\
H THF

S"
(5"6 Synthesis of 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methoxy)-2-methyl-N-(5-methylthiazol-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(5-methylthiazol-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (meloxicam, 246 mg, 0.7 mmol) and tiphenylphosphine (PPh3, 190 mg, 0.73 mmol) were added to tetrahydrofuran (3.4 mL) under nitrogen. After cooling to -10 C, diisopropyl azodicarboxylate (DIAD, 148 mg, 0.73 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 min, the mixture was allowed to warm to room temperature. 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitile (170 mg, 0.5 mmol) was added and the stirring continued. The reaction was monitored by TLC. After complete exhaust of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9:
1) to give the title compound as a yellow solid, 0.009 g, 2.6% yield. MS (m/z): [M+H] calcd for C311-133N90552, 676.20, found 676.2.1H NMR (400 MHz, Chloroform-d) .3 14.01 (s, 1H), 8.28 (s, 1H), 8.03 (dd, J = 7.6, 1.4 Hz, 1H), 7.84 (dd, J = 7.4, 1.5 Hz, 1H), 7.73 ¨ 7.52 (m, 3H), 7.30 (d, J = 4.5 Hz, 1H), 6.51 (dd, J = 11.0, 3.8 Hz, 1H), 6.42 (s, 2H), 5.01 (d, J = 26.1 Hz, 1H), 4.04 (dd, J = 13.2, 4.2 Hz, 1H), 3.86 ¨ 3.68 (m, 1H), 3.64 (dd, J = 13.2, 8.7 Hz, 1H), 3.56 ¨ 3.39 (m, 3H), 3.29 (d, J = 18.7 Hz, 3H), 3.09 (s, 3H), 2.53 ¨2.39 (m, 1H), 2.21 (d, J = 1.4 Hz, 3H), 2.00 ¨ 1.80 (m, 1H), 1.73 ¨
1.63 (m, 1H), 1.02 (dd, J = 9.5, 7.1 Hz, 3H).
Example 143 3-((35, 4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile r\li, cc N
OH
) I __________________________ EDCI,DMAP,DCM
CN) (j Synthesis of 3-((35, 4R)-3-methyl-6-(7-(2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoy1)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile 3-((3S, 4R)-3-methyl-6-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1, 6-diazaspiro [3.4] oct-1-y1)-3-oxopropanenitrile (delgocitinib, 75 mg, 0.24 mmol), 4-dimethylamino pyridine (DMAP, 30 mg, 0.24 mmol), 2-(4-(1-oxoisoindolin-2-y1) phenyl) butanoic acid (indobufen, 92 mg, 0.31 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30: 1 to 10: 1) to give the title compound as a white solid, 0.018 g, 12.7% yield. MS (m/z): [M+H] calcd for C34H33N703, 588.26, found 588Ø1H NMR
(400 MHz, Chloroform-d) 8.37 (s, 1H), 7.86 ¨ 7.79 (m, 1H), 7.70 (dd, J = 8.7, 1.1 Hz, 2H), 7.60 (dd, J
= 4.2, 1.5 Hz, 1H), 7.56 ¨ 7.46 (m, 3H), 7.46 ¨ 7.39 (m, 2H), 6.55 (t, J = 4.1 Hz, 1H), 5.93 (t, J = 7.5 Hz, 1H), 4.74 (s, 2H), 4.26 (t, J = 8.4 Hz, 1H), 4.16 (dd, J = 12.0, 8.2 Hz, 1H), 4.12¨ 3.94 (m, 2H), 3.73 (s, 1H), 3.62 (ddd, J = 8.4, 6.0, 2.4 Hz, 1H), 3.14 (d, J =
3.0 Hz, 2H), 2.81 (ft, J = 13.0, 5.9 Hz, 1H), 2.67 (s, 1H), 2.22 (dt, J =
14.2, 7.3 Hz, 1H), 2.09 (s, 1H), 1.96 ¨ 1.86 (m, 1H), 1.16 (dd, J = 7.1, 4.4 Hz, 3H), 0.92 (td, J = 7.3, 1.2 Hz, 3H).
Example 144 (4-((35, 4R)-1-(2-cyanoacety1)-3-methyl-1, 6-diazaspiro [3.4] octan -6-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate N
/C-AN
N

jo( Nr1 0 OH
SEMCI DIPEA DCM TFA DCM,r t N
EDCI DMAP, DCM 0-1 crejN N

_8.
=
First step: synthesis of 3-((3S, 4R)-3-methyl-6-(7-02-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile Under nitrogen protection, 3-((3S, 4R)-3-methyl-6-(7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1, 6-diazaspiro [3.4]
oct-1-y1)-3-oxopropanenitrile (Delgocitinib, 200 mg, 0.644 mmol) and N, N-diisopropylethyl amine (0.17 mL, 0.966 mmoL) were added in dichloromethane (2 mL). After stirring at room temperature for half an hour, (2-(chloromethoxy) ethyl) trimethylsilane (140 mg, 0.838 mmol) was added in an ice water, and stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 200: 1 to 20: 1) to give the title compound, 0.234 g, 82.5% yield. MS (m/z):
[M+H] calcd for C22H32N602Si, 441.24;found, 441.2.
Step 2: synthesis of 3-((35, 4R)-6-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile Trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of 3-((35, 4R)-3-methyl-6-(7((2-(trimethylsily1) ethoxy) methyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1)-1, 6-diazaspiro [3.4]
oct-l-y1)-3-oxopropanenitrile (0.234 g, 0.53 mmol) in dichloromethane (15 mL) under nitrogen in an ice-water bath. After half an hour, the ice-water bath was removed and the temperature was raised to room temperature and stirring was continued for 2 hours. Saturated sodium bicarbonate solution was added to the above reaction solution at 0 C to adjust the pH to 8. Then the mixture was poured into a separating funnel for separation. The organic layer was washed with a saturated salt water solution and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 50: 1 to 9: 1) to give the title compound, 0.055 g, 30.4% yield. MS (m/z): [M+H] calcd for C17H20N602, 341.16;found, 341.1.
Step 3: synthesis of (4-(14(R)-2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methyl (S)-2-(4-isobutylphenyl) propanoate 3-((3S, 4R)-6-(7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methy1-1, 6-diazaspiro [3.4] octan -1-y1)-3-oxopropanenitrile (55 mg, 0.16 mmol), 4-dimethylamino pyridine (DMAP, 19 mg, 0.16 mmol), (S)-(+)-2-(4-isobutylphenyl) propanoic acid((S)-(+)-ibuprofen, 32 mg, 0.17 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 50 mg, 0.26 mmol) were dissolved in a mixed solvent of dichloromethane (1 mL) and dimethylformamide (0.25 mL) and stirring was continued for 16 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered.
The solvent was evaporated under reduced pressure to obtain the crude product.
The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30:
1 to 10: 1) to give the title compound as a white solid, 0.02 g, 23.6% yield. MS (m/z): [M+H] calcd for C30H36N603, 529.28, found 529.2.1H
NMR (400 MHz, Chloroform-d) .3 8.28 (s, 1H), 7.09 ¨ 6.92 (m, 5H), 6.45 (d, J=
3.7 Hz, 1H), 6.10 (d, J= 10.6 Hz, 1H), 6.01 (d, J= 10.6 Hz, 1H), 4.31 ¨4.14 (m, 2H), 4.03 (d, J= 11.9 Hz, 2H), 3.77 (s, 1H), 3.67 ¨ 3.59 (m, 2H), 3.16 (s, 2H), 2.83 (dt, J= 13.0, 7.5 Hz, 1H), 2.67 (h, J= 7.0 Hz, 1H), 2.35 (d, J= 7.2 Hz, 2H), 2.10 (s, 1H), 1.75 (dt, J= 13.5, 6.7 Hz, 1H), 1.38 (d, J= 7.2 Hz, 3H), 1.18 (d, J= 2.8 Hz, 3H), 0.81 (d, J= 6.7 Hz, 6H).
Example 145 3-((3S, 4R)-6-(7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile OH

EDCI,DMAP,DCM

Synthesis of 3-((3S, 4R)-6-(7-(2-(3-benzoylphenyl) propanoy1)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-3-methyl-1, 6-diazaspiro [3.4] oct -1-y1)-3-oxopropanenitrile 3-((35, 4R)-3-methyl-6-(7H-pyrrolo [2, 3-d] pyrimidin -4-y1)-1, 6-diazaspiro [3.4] oct-l-y1)-3-oxopropanenitrile (Delgocitinib, 75 mg, 0.24 mmol), 4-dimethylamino pyridine (DMAP, 30 mg, 0.24 mmol), 2-(3-benzoylphenyl) propanoic acid (ketoprofen, 79 mg, 0.31 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDCI, 70 mg, 0.36 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water and saturated salt water solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/methanol = 30: 1 to 10: 1) to give the title compound as a white solid, 0.038 g, 29% yield. MS (m/z):
[M+H] calcd for C32H30N603, 547.24, found 547.1.41 NMR (400 MHz, Chloroform-d) .3 8.35 (s, 1H), 7.94 (s, 1H), 7.81 ¨ 7.63 (m, 5H), 7.61 ¨ 7.55 (m, 1H), 7.50 ¨ 7.43 (m, 2H), 7.40 (t, J = 7.7 Hz, 1H), 6.65 (dd, J = 4.3, 1.5 Hz, 1H), 6.19 (q, J = 7.0 Hz, 1H), 4.32 (t, J = 8.4 Hz, 1H), 4.24 (dd, J = 12.1, 7.2 Hz, 1H), 4.14 (s, 1H), 4.04 (dd, J =
12.1, 8.4 Hz, 1H), 3.85 ¨3.77 (m, 1H), 3.69 (dd, J = 8.3, 5.9 Hz, 1H), 3.21 (d, J = 2.7 Hz, 2H), 2.93 ¨ 2.80 (m, 1H), 2.78 ¨ 2.68 (m, 1H), 2.17 (dq, J =

13.2, 7.3 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H), 1.26¨ 1.19 (m, 3H).
Example 146 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide N' 'a rCN

I
-1\1 / I
cri) N' rCI\I
OH 0 n N N

/ N N DIAD,PPh3 ,N H L.0 0 Jo S s \--OH 61) THF
S S-1\1 6"6 Synthesis of 4-((4-(((3R, 4R)-1-(2-cyanoacety1)-4-methylpiperidin-3-y1) (methyl) amino)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (tenoxicam, 98 mg, 0.292 mmol) and triphenylphosphine (PPh3, 230 mg, 0.876 mmol) were added to tetrahydrofuran (2 mL) under nitrogen. Diisopropyl azodicarboxylate (DIAD, 88 mg, 0.438 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature. 3-((3R, 4R)-3((7-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino)-4-methylpiperidin-1-y1)-3-oxopropanenitrile (100 mg, 0.292 mmol) was added and stirring was continued.
The reaction was monitored by TLC. After complete exhaust of the starting material (1 h), the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9: 1) to give the title compound as a yellow solid, 0.011 g, 5.6% yield. MS (m/z): [M+H] calcd for C301-131N90552, 662.19, found 662.2.1H NMR (400 MHz, DMSO-d6) .3 16.02 (s, 1H), 8.63 (t, J = 10.2 Hz, 1H), 8.38 ¨ 8.23 (m, 2H), 8.19 ¨ 8.10 (m, 1H), 8.06 (dd, J = 5.2, 2.2 Hz, 1H), 7.75 (dd, J = 6.7, 3.8 Hz, 1H), 7.49 (dd, J = 5.2, 1.8 Hz, 1H), 7.25 ¨ 7.17 (m, 1H), 6.81 ¨ 6.63 (m, 3H), 4.85 (s, 1H), 4.19 ¨ 3.88 (m, 3H), 3.81 ¨ 3.59 (m, 3H), 3.27 (d, J = 3.8 Hz, 3H), 2.99 (d, J = 2.0 Hz, 3H), 2.41 ¨2.33 (m, 1H), 1.90¨ 1.69 (m, 1H), 1.63 ¨ 1.56 (m, 1H), 1.00 (d, J = 7.1 Hz, 3H).
Example 147 2-Methyl-4-((4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-N-(pyridin-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide c),µ
.s HN
1\01 0) 0 Nr\J
,N H
µ0 CZ\
,S
(:),\
H OH 0 Nk7j:1) N DIAD,PPh3 N
s H

N N HF
\¨OH 0 0 N H
S' cro Synthesis of 2-methyl-4-((4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-N-(pyridin-2-y1)-2H-benzo [e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(pyridin-2-y1)-2H-benzo [e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (piroxicam, 122 mg, 0.368 mmol) and triphenylphosphine (PPh3, 214 mg, 0.817 mmol) were added to tetrahydrofuran (3 mL) under nitrogen. After cooling to -10 C, diisopropyl azodicarboxylate (DIAD, 124 mg, 0.613 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature. 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d] pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methylmethane sulfonamide (150 mg, 0.409 mmol) was added and the stirring was continued. The reaction was monitored by TLC. After complete exhaust of the starting material, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9: 1) to give the title compound as a yellow solid, 0.012 g, 4.8% yield. MS (m/z): [M+H] calcd for C311-136N80652, 681.22, found 681.2.1H NMR (400 MHz, Chloroform-d) .3 15.31 (s, 1H), 8.59 (d, J = 6.6 Hz, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.32 (s, 1H), 8.10 (dd, J = 7.7, 1.4 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J = 7.6, 1.4 Hz, 1H), 7.77 ¨ 7.61 (m, 3H), 6.85 ¨6.65 (m, 2H), 6.55 (d, J = 3.8 Hz, 1H), 5.40 ¨ 5.31 (m, 2H), 4.69 (s, 1H), 3.19 (s, 3H), 3.10 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 2.82 (d, J = 5.3 Hz, 3H), 2.19 ¨ 2.11 (m, 2H), 2.02¨ 1.94(m, 1H), 1.90 ¨ 1.65 (m, 4H), 1.37¨ 1.27 (m, 2H).
Example 148 4-04-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide -o s' o- CN
N-N
N
kN N\

N N

.0 0- = CN
Nqj -3' 0' CN
N-N

N-N DIAD PPh H
N N
N
kr\r N, d -------HO) H
'µo Synthesis of 4-04-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl) azetidin -3-y1)-1H-pyrazol-4-y1)-7H-pyrrolo [2, 3-d]
pyrimidin -7-y1) methoxy)-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (tenoxicam, 75 mg, 0.224 mmol) and triphenylphosphine (PPh3, 196 mg, 0.748 mmol) were added to tetrahydrofuran (2 mL) under nitrogen. After cooling to -10 C, diisopropyl azodicarboxylate (DIAD, 75 mg, 0.374 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature naturally. 2-(1-(Ethylsulfony1)-3-(4-(7-(hydroxymethyl)-7H-)) pytolo [2, 3-d] pyrimidin -4-y1)-1H-pyrazol-1-y1) azetidin -3-y1) acetonitile (100 mg, 0.249 mmol) was added and the stirring was continued. The reaction was monitored by TLC. After complete exhaust of the starting material, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9: 1) to give the title compound as a yellow solid, 0.008 g, 4.9% yield. MS (m/z): [M+H] calcd for C301-128N100653, 721.14, found 721.2.1H NMR (400 MHz, Chloroform-d) .3 13.45 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.25 (s, 1H), 8.18 ¨ 8.08 (m, 2H), 7.65 ¨ 7.56 (m, 2H), 7.44 ¨ 7.31 (m, 2H), 6.90 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 6.60 (d, J = 3.7 Hz, 1H), 6.17 (s, 2H), 4.56 (d, J = 9.2 Hz, 2H), 4.18 (d, J = 9.2 Hz, 2H), 3.35 (s, 2H), 3.12 ¨ 2.99 (m, 5H), 1.35 (td, J
= 7.5, 3.8 Hz, 3H).
Example 149 2-Methyl-4-((4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d]

pyrimidin -7-y1) methoxy)-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide H
N
N ) N
µ0 (:),\

H

p=-= N N DIAD,PPh3 tt. N7 N
H
N (31) THF 0 0 \--OH
N N
Olp Synthesis of 2-methyl-4-((4-(methyl ((trans)-4-((N-methylsulfamoyl) methyl) cyclohexyl) amino)-7H-pyrrolo [2, 3-d] pyrimidin -7-y1) methoxy)-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 21 thiazine -3-carboxamide 1, 1-dioxide 4-Hydroxy-2-methyl-N-(pyridin-2-y1)-2H-thieno [3, 2-e] [1, 2] thiazine -3-carboxamide 1, 1-dioxide (tenoxicam, 75 mg, 0.224 mmol) and triphenylphosphine (PPh3, 196 mg, 0.748 mmol) were added to tetrahydrofuran (2 mL) under nitrogen. After cooling to -10 C, diisopropyl azodicarboxylate (DIAD, 75 mg, 0.374 mmol) was added dropwise to the mixture with stirring. After stirring at -10 C for 20 minutes, the mixture was allowed to warm to room temperature naturally. 14(Trans)-447-(hydroxymethyl)-7H-pyrrolo [2, 3-d]
pyrimidin -4-y1) (methyl) amino) cyclohexyl)-N-methylmethane sulfonamide (100 mg, 0.272mm01) was added and the stirring was continued. The reaction was monitored by TLC. After complete exhaust of the starting material, the solvent was evaporated under reduced pressure to give the crude product. The crude product was further separated by silica gel column chromatography (dichloromethane/acetonitrile = 20: 1 to 9: 1) to give the title compound as a yellow solid, 0.006 g, 3.9% yield. MS (m/z): [M+H] calcd for C29H34N80653, 687.18, found 687.2.1H NMR (400 MHz, Chloroform-d) .3 8.89 (s, 1H), 8.29 ¨ 8.16 (m, 1H), 8.03 (s, 1H), 7.82 (dt, J
= 8.4, 1.0 Hz, 1H), 7.54 (ddd, J = 8.5, 7.4, 1.9 Hz, 1H), 7.00 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 6.90 (d, J = 3.8 Hz, 1H), 6.42 (d, J = 3.8 Hz, 1H), 6.16 (s, 2H), 4.59 ¨4.39 (m, 1H), 3.24 (d, J = 5.0 Hz, 1H), 3.16 (s, 3H), 3.04 (d, J =

14.0 Hz, 3H), 2.98 (d, J = 6.3 Hz, 2H), 2.85 (dd, J = 5.3, 3.6 Hz, 3H), 2.19 (d, J = 12.8 Hz, 3H), 2.03 (q, J = 6.2 Hz, 1H), 1.92¨ 1.59 (m, 4H), 1.43 ¨ 1.33 (m, 2H).
Analysis method for hydrolysis rate of compounds of the present invention 1. Preparation of standard working curve solution About 10 mg of JAK inhibitors (tofacitinib and baricitinib) reference substances were weighed into a 25 mL
volumetric flask, acetonitrile/water = 7/3 (v/v) was added to dissolve and dilute to the marked volume, serving as a stock solution. The stock solution was diluted with a suitable dilution factor to obtain linear solutions of each concentration: 0.0002 mg/mL, 0.0004 mg/mL, 0.004 mg/mL, 0.04 mg/mL, and 0.08 mg/mL.
About 10 mg of JAK inhibitors (Oclacitinib, Ruxolitinib, Delgocitinib, and Upadacitinib) reference substances were weighed into a 25 mL volumetric flask, acetonitrile/water = 7/3 (v/v) was added to dissolve and dilute to the marked volume, serving as a stock solution. The stock solution was diluted with a suitable dilution factor to obtain linear solutions of each concentration: 0.0002 mg/mL, 0.0004 mg/mL, 0.004 mg/mL, 0.04 mg/mL, and 0.08 mg/mL.
2. Preparation of sample solution About 5 mg of the sample (the compound prepared in the present invention) was weighed into a 20 mL volumetric flask, acetonitrile/water = 7/3 (v/v) was added to dissolve and dilute to the marked volume, serving as a stock solution. An appropriate amount of HPLC was loaded as the 0-day sample. The test solution was sealed with a sealing film and placed in a 37 C constant temperature shaker. The test samples were taken at the same time on days 1, 2, 3, and 4 respectively, the release amount of JAK inhibitor in the sample was calculated according to the sample weight and JAK inhibitor standard curve.
3. Calculation formula % Release of JAK Inhibitor wherein Atm( inhibitor is the peak area of JAK inhibitor in a is the slope of the standard curve the sample chromatogram b is the intercept of the standard curve W is the sample weight (mg) M1 is the molecular weight of the sample M2 is the molecular weight of the JAK
inhibitor 4. Chromatographic conditions The chromatographic conditions of the test are shown in Table 2.
Table 2 Chromatographic conditions WatersXbridge Shield RP18,150 x 4.6mm, 3.5 gm Chromatographic column Flow rate (LPM) 0.8 mL/min Column temperature Detection 220nm Loading volume 5 gL
wavelength Mobile phase 10mM KH2PO4(Adjust pH6.5 with KOH)/ACN=9/1(v/v); B:
ACN
Time 0 10 16 17 22 Elution gradient A% 85 20 20 85 85 B% 15 80 80 15 15 Table 3 shows the drug release rate results of the compound drugs prepared in the above examples of the present disclosure.
Table 3 Drug Release Rate Table Ex. No. Release Rate (%/day) Ex. 1 8.26 Ex. 2 8.5 Ex. 3 0.05 Ex. 4 3.32 Ex. 5 4.7 Ex. 6 9.82 Ex. 7 15.65 Ex. 8 14.77 Ex. 9 13.49 Ex. 10 11.25 Ex. 11 9.17 Ex. 12 18.94 Ex. 13 12.18 Ex. 14 0.98 Ex. 15 1.86 Ex. 16 39.31 Ex. 17 2.44 Ex. 18 2.97 Ex. 19 6.25 Ex. 20 5.06 Ex. 21 4.6 Ex. 22 2.75 Ex. 23 7.63 Ex. 24 5.96 Ex. 25 0.68 Ex. 26 36.19 Ex. 27 7.48 Ex. 28 2.98 Ex. 29 7.08 Ex. 30 1.63 Ex. 31 3.08 Ex. 32 7.12 Ex. 33 5.01 Ex. 34 1.57 Ex. 35 4.57 Ex. 36 14.98 Ex. 37 1.05 Ex. 38 18.42 Ex. 39 10.11 Ex. 40 0.62 Ex. 41 4.27 Ex. 42 22.18 Ex. 43 2.99 Ex. 44 10.18 Ex. 45 1.93 Ex. 46 25.52 Ex. 47 0.36 Ex. 48 0.03 Ex. 49 0.11 Ex. 50 0.05 Ex. 51 0.35 Ex. 52 0.1 Ex. 53 0.06 Ex. 54 4.93 Ex. 55 0.16 Ex. 56 0.07 Ex. 57 0.57 Ex. 58 12.46 Ex. 59 0.15 Ex. 60 <0.01 Ex. 61 <0.01 Ex. 62 0.01 Ex. 63 0.02 Ex. 64 0.88 Ex. 65 0.01 Ex. 66 0.06 Ex. 67 0.02 Ex. 68 10.6 Ex. 69 0.03 Ex. 70 0.42 Ex. 71 0.01 Ex. 72 <0.01 Ex. 73 0.2 Ex. 74 0.44 Ex. 75 10.38 Ex. 76 0.05 Ex. 77 3.69 Ex. 78 6.27 Ex. 79 7.38 Ex. 80 27.29 Ex. 81 0.013 Ex. 82 0.43 Ex. 83 0.003 Ex. 84 0.06 Ex. 85 0.61 Ex. 86 <0.01 Ex. 87 0.01 Ex. 88 0.17 Ex. 89 0.16 Ex. 90 0.35 Ex. 91 1.65 Ex. 92 0.82 Ex. 93 0.83 Ex. 94 0.72 Ex. 99 0.21 Ex. 100 0.24 Ex. 104 0.45 Ex. 105 0.17 Ex. 107 0.22 Ex. 110 0.08 Ex. 113 0.42 Ex. 116 0.42 Ex. 117 0.08 Ex. 120 0.42 Ex. 122 15.32 Ex. 123 3.02 Ex. 124 2.75 Ex. 125 6.17 Ex. 126 7.80 Ex. 130 11.67 Ex. 131 3.56 Ex. 133 10.13 Ex. 138 2.15 Ex. 140 8.10 Ex. 142 0.05 Ex. 143 4.29 Ex. 144 0.05 As can be seen from the results in Table 3 above, the coupling of an anti-inflammatory drug compound containing a carboxylic acid or hydroxyl group with a JAK inhibitor compound to form a coupling compound having an acyloxy group and or methoxy group according to the present invention has a high therapeutic effect and a special effect of controlled-release drug activity.
Pharmacodynamic Evaluation Studies of Compounds of the Invention Efficacy evaluation study of ointment transdermal patch formulated by compounds using IMQ-induced psoriasis mouse model Experimental design BALB/c mice (male) aged 6-8 weeks were selected to have depilated back skin with an area of 2 x 3cm. 5% IMQ
cream 62.5 mg was applied once a day for 9 consecutive days for model induction. Mice were housed in an SPF-grade animal room in IVC cages at a temperature of 20-26 C and a humidity of 40-70% under a 12-hour light-dark cycle. Diet ad libitum, except where fasting is required.
Mice were randomly divided into groups, a number of 8 mice, administration concentration 20 mg/g, administration amount 50 mg, administration route, and frequency: skin smear, BID. The positive control was compound dexamethasone acetate (Dex) cream which is a commercially available product with a Dex content of 0.75mg/g (999 Piyanping, Sanjiu Pharmaceutical). Dosing started from day 1(the first day) (the day of model induction) to day 9.
2. Preparation of test ointment Topical preparations are mostly semi-solid dosage forms. The base and solvent of a semi-solid dosage form are generally widely used in medicine and daily chemical products. The excipients which can be added are also the common excipients in the manual of excipients. Therefore, the patent compounds are prepared into corresponding test ointments. The ointment compound was dissolved with diisopropyl adipate to prepare a vaseline-based ointment. In order to improve the stability of the ointment, microcrystalline cellulose was added as an excipient in the formulation. The white vaseline has a melting point of 45-60 C. The solution, white vaseline, and microcrystalline cellulose are thoroughly mixed while the vaseline is in a molten state. After cooling to solidification, it was divided into an aluminum ointment, and the specific weight ratios of base, solvent, and excipients are shown in Table 4.
Table 4. Composition of ointment formulations for efficacy experiments Cmpd No. CPD-002 CPD-017 CPD-027 CPD-028 Compound 2 2 2 2 percentage Solvent 15 15 15 15

15 percentage Matrix 80 80 80 80 percentage Excipient 3 3 3 3 3 Percentage Total (w/w) 100 100 100 100 3. Model Evaluation Dorsal modeling site skin PASI was performed on the experimental animals. The scoring criteria are shown in Table 5 below:
Table 5 Scoring criteria Score Erythema Dandruff Skin thickening 0 Normal Normal Normal 1 Mild Mild: small amount of shavings Mild Moderate: a large amount of 2 Moderate Moderate scurf 3 Severe Severe: skin scab Severe Extremely 4 Extremely severe: heavy scab Extremely severe severe Statistical analysis of PASI scores was performed using Two-way ANOVA. All data were analyzed using GraphPad Prism 8.0 software with a p <0.05 significant difference (*, p <0.05;
**, p<0.01).
4. Efficacy PASI Score Curve The PASI score curves of CPD-029, CPD-028, CPD-027, CPD-017, and CPD-002 compared with the model group, excipient group, and Dex cream group are shown in Figs 1, 2, 3, 4, and 5, respectively. Among them, the model group was treated with 62.5 mg of 5% IMQ cream applied to the back skin of mice once daily to induce psoriasis, and the excipient group was treated with 15% (w/w) diisopropyl adipate, 80% vaseline, and 3%
microcrystalline cellulose.
As can be seen from Figs. 1-5, the Dex cream group (0.75 mg/g) had a significant therapeutic effect on day4-day10 (days 4-10) compared with the excipient group; CPD-017, CPD-027, CPD-028, and CPD-029 had a significant therapeutic effect in day 5-day 10 (days 5-10); CPD-002 had a significant therapeutic effect in day 4 day 8 (days 4-8).

Claims

Claims 1. An anti-inflammatory compound, or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, having a structure shown in general formula (I):
A-Y-B (I) wherein, A is a group after dehydrogenation of an amine compound having JAK
inhibitory activity;
Y is a direct connection; or-(CH2)-0-or-(CH2)-;
B is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1, or a group formed by means of dehydrogenation of a hydroxy-containing compound B2; and wherein, in the case where the carboxylic acid Bi is dehydroxylated to form a group, the Y group is a direct connection or -(CH2)-0-; in the case where the hydroxy-containing compound B2 is dehydrogenated to form a group, the Y group is-(CH2)-.
2. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, having a structure shown in general formulas (II) or (Ha):
wherein RI is selected from pyrazolyl or pyrrolyl unsubstituted or substituted with Ra; or -N(CH3)-Cy; RIa represents a pyrrole ring substituted by a halogen-substituted C1-C6 alkylaminoacyl group and/or by a Ci-C6 alkyl group;
Cy is a five-or six-membered carbocyclic ring or a five-or six-membered nitrogen-containing heterocyclic ring unsubstituted or substituted by Rb; R. and Rb are each independently groups containing at least one or two groups selected from a group consisting of an acyl group, a dithioy I group, a cyano group, an amino group or a C i-C 6 alkyl-substituted amino group, and a four-, five-, or six-membered nitrogen-containing heterocyclic group, or the Date regue/Date received 2024-01-09 nitrogen-containing heterocyclic group substituted with C1-C6 alkyl;
preferably Ra and Rb are each independently groups which consist of one group of acyl or dithioacyl and at least one group selected from a group consisting of cyano, amino or Ci-C6 alkyl substituted amino and a four-, five-, or six-membered nitrogen-containing heterocyclyl, or the nitrogen-containing heterocyclyl substituted with C1-C6 alkyl, wherein the C1-C6 alkyl is substitutable by halogen;
R2 in both general formulas (11) and (11a) is -B, i.e. is a group formed by means of dehydroxylation of a carboxy-containing carboxylic acid compound B1 and is selected from R4-Ar-R3-00-, wherein, R3 is selected from Ci-C6 alkylene; -NH-, R5NH-, or Ci-C6 alkylene substituted with a Ci-C6 alkoxyamide group; or a direct connection, i.e. the Ar group is directly linked to -CO-;
R3 is preferably methyl substituted or unsubstituted methylene, -C2114-, or a direct connection; R5 1S C1-C6 alkylene; wherein the C1-C6 alkylene is substitutable by halogen (preferably halogen is one or two or more selected from a group consiting of fluorine, chlorine and bromine);
Ar is an aromatic ring group, preferably selected from a benzene ring; a naphthalene ring or an aryl heterocyclic ring; and a benzene ring, a naphthalene ring, or an aryl heterocyclic ring or an aryl fused heterocyclic ring (here, the aryl heterocyclic ring being preferably a nitrogen-containing or oxygen-containing benzo heterocyclic ring such as a benzopyrrole ring) substituted with one or more groups selected from halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 acyl group, or a C1-C6 alkoxy group; Ar is more preferably an aryl heterocyclic ring containing a nitrogen atom; and R4 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl containing C1-C6 cycloalkanoyl, C1-C6 alkylamido or aryl fused heterocyclic amido, C1-C6 carbonyloxy, halogen substituted benzoyl, C1-C6 alkyl or halogen substituted or unsubstituted phenoxy, C1-C6 alkyl or halogen substituted or unsubstituted phenyl or aryl fused heterocyclic ring, C1-C6 alkyl or halogen substituted or unsubstituted phenylamino, or R4 can also be absent; wherein the C1-C6 alkoxy can also form a bridged ring with Ar.
3. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 2, wherein Cy is substituted cyclohexyl or substituted piperidinyl; preferably, the substituted cyclohexyl group is a cyclohexyl group substituted with an amino group and a dithio group, and the substituted piperidinyl group is a piperidinyl group substituted with an acyl group or a dithio group and -CN.
4. The compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 1-3, wherein the compound is a coupling compound resulting from a condensation reaction of an amine compound A with a carboxylic acid compound B
i.
5. The compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 1-4, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups:
tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:

preferably A is a group formed after dehydrogenation of tofacitinib, ruxolitinib and baricitinib.
6. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 2-5, wherein -B1 is a group after dehydroxylation of a carboxylic acid moiety selected from a group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:
7. The anti-inflammatory compound, or the stereoisomer, tautomer, N-oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the compound is a coupled compound obtained by condensation reaction of an amine compound A selected from the group consisting of tofacitinib, baricitinib, oclacitinib, upadacitinib, ruxolitinib and delgocitinib with a carboxylic acid compound B1 selected from the group consisting of ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, etodolac, actarit and indomethacin; preferably, the amine compound is tofacitinib, ruxolitinib and baricitinib.
8. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds:

9. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following specific compounds:
10. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 6, wherein the compound is any one of the following 1 1. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1, having a structure shown in general formulas (III) :
wherein R1 has the same meaning as R1 in general formula (II); Rh, has the same meaning as Ria in formula (lla);
R2' in formula (III) and formula (Ma) are both Y-B, B is Bi in formula (II) or (Ila), or B is B2; wherein the group -B1 is a group formed by dehydroxylation of a carboxylic acid compound B1 and Y-is (CH2)-0-; the group -B2 is a group formed by dehydrogenation of a hydroxyl-containing compound B2 and Y- is-(CH2)-; the group -B1 has the same meaning as the R2 group in formula (II) or in formula (Ha); the group -B2 is Rc-CO-NH-R3, wherein Itc is a 4-hydroxy-benzothiazine dioxide-3-y1 represented by the following structural formula (a),(wherein the phenyl ring may be substituted by halogen or Ci-C6 alkyl), or a 4-hydroxy-Re substituted thienothiazine dioxide-3-y1 represented by the following structural formula (b), wherein -CO-NII-Rd is bonded at the 3-position of the thiazine ring, wherein Rd is thiazole, isothiazole, oxazole, isoxazole, or pyridine or the group thereof substituted with Ci-C6 alkyl or halogen, preferably a thiazole or isoxazole substituted with methyl; and unsubstituted pyridyl; Re is Ci-C6 alkyl or halogen (preferably halogen is one or two or more selected from a group consisting of fluorine, chlorine, or bromine); a arrow next to Re in formula (b) indicates that its substitution position on the thiophene ring may be any carbon-linked hydrogen atom capable of undergoing substitution.
12. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 1 1, wherein -B1 is a group after dehydroxylation of any one of carboxylic acids selected from a group consisting of the following groups:
ibuprofen, (S)-(+)-ibuprofen, naproxen, fenoprofen, flurbiprofen, loxoprofen, ketoprofen, diclofenac, etodolac, actarit, indomethacin, N-Boc-L-phenylglycine, aspirin, indobufen, mefenamic acid and tolfenamic acid:
-B2 is a group after dehydrogenation of a hydroxyl-containing compound of one of the following specific compounds:
13. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 11 or 12, obtained by a preparation method comprising the steps of:
2) reacting A-C112-0H compound with an acyl chloride of B or directly with the B compound;
wherein the A-CH2-0H compound is preferably prepared by the following step 1):
reacting the amine compound A
to form the A-CH2-0H compound.
14. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 13, wherein A- is a group after dehydrogenation of an amine compound selected from a group consisting of any one of the following groups:
tofacitinib, baricitinib, oclacitinib, ruxolitinib, upadacitinib and delgocitinib:
preferably A is a group formed after dehydrogenation of tofacitinib, ruxolitinib and baricitinib.

15. The anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of claim 14, wherein the compomd is any one of the following specific compounds:

16. A method for preparing the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 2-10, comprising the steps of:
subjecting A and B to a condensation reaction of the loss of water in the presence of a catalyst and an organic solvent.
17. The preparation method of claim 16, wherein the catalyst is one or two or more of EDCI (1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride)), DCC (dicyclohexyl carbodiimide), CDI (N, N-carbonyldiimidazole), DMTMM (4-(4, 6-dimethoxytriazine)-4-methylmorpholine hydrochloride), HATU (2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate), HCTU
(6-chlorobenzotriazole-1, 1, 3, 3-tetramethyluronium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) and NPC; preferably the organic solvent is one or two or more selected from a group consisting of DCM (dichloromethane), DMF (dimethylformamide), petroleum ether, acetone, chloroform, ethyl acetate, acetonitrile and THF (tetrahydrofuran), more preferably dichloromethane and/or dimethylformamide;
further preferred, the reaction is carried out in the presence of a basic substance, wherein the basic substance is preferably one or two or more selected from a group consisting of DMAP
(dimethylamino pyridine), triethylamine, DIPEA (N, N-diisopropylethyl amine) and hydroxides or salts of sodium, potassium, lithium and ammonium.
18. A method for preparing the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 11-15, comprising the steps of: subjecting A-CH2OH and B to a condensation reaction on the loss of water.
19. Use of the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 1-15, in the preparation of anti-inflammatory drug preparations or drug compositions (preferably external drug compositions).
20. An anti-inflammatory drug preparation or drug composition (preferably external drug compositions) including the anti-inflammatory compound, or the stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof of any one of claims 1-15.